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

  1. Roy Rabbie1,
  2. Sheena Derry2,*,
  3. R Andrew Moore2

Editorial Group: Cochrane Pain, Palliative and Supportive Care Group

Published Online: 30 APR 2013

DOI: 10.1002/14651858.CD008039.pub3


How to Cite

Rabbie R, Derry S, Moore RA. Ibuprofen with or without an antiemetic for acute migraine headaches in adults. Cochrane Database of Systematic Reviews 2013, Issue 4. Art. No.: CD008039. DOI: 10.1002/14651858.CD008039.pub3.

Author Information

  1. 1

    Epsom and St Helier University Hospitals NHS Trust, Department of Respiratory Medicine, London, UK

  2. 2

    University of Oxford, Pain Research and Nuffield Department of Clinical Neurosciences (Nuffield Division of Anaesthetics), Oxford, Oxfordshire, UK

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

Publication History

  1. Publication Status: Stable (no update expected for reasons given in 'What's new')
  2. Published Online: 30 APR 2013

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Characteristics of included studies [ordered by study ID]

MethodsMulticentre, randomised, double-blind, placebo-controlled, parallel-group. Single oral dose

Medication taken when migraine of moderate or severe intensity

Assessments at 0, 0.5, 1, 1.5, 2, 3, 4, 5, and 6 hours

If pain not controlled, participants asked to wait 2 hours before taking rescue medication (of participant's choice)


ParticipantsMigraine with/without aura (IHS 1988) of at least moderate severity. History: 0.5 to 6 episodes/month in the year before study entry

Excluded participants with > 50% episodes requiring bedrest or > 20% including vomiting

Prophylactic medication continued unchanged, if stable

N = 660

M 104, F 556

Mean age 39 years

History of aura: 27%


InterventionsIbuprofen 200 mg, n = 216

Ibuprofen 400 mg, n = 223

Placebo, n = 221


OutcomesPain-free at 2 hours

Headache relief at 1 and 2 hours

Use of rescue medication

Presence of nausea, vomiting, photophobia, phonophobia

Functional disability

Adverse events

Withdrawals


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


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk"computer-generated randomization code"

Allocation concealment (selection bias)Low risk"unopened treatment-blinding tear-off portion of winged label was affixed to the patient's case report form"

Blinding (performance bias and detection bias)
All outcomes
Low riskAll participants "received a blister card containing two tablets that were identical in colour, size, and shape"

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

Study sizeLow risk> 200 participants per treatment group


MethodsMulticentre, randomised, double-blind (double-dummy), placebo-controlled, three-period, cross-over. Single oral dose of each treatment for each of three migraine attacks, with at least 48 hours between consecutive treatments

Medication taken within 6 hours of onset, when migraine of moderate or severe intensity, and not improving

Assessments at 0, 0.5, 1, 1.5, 2, and 24 hours

If pain not controlled, participants asked to wait 2 hours before taking rescue medication (of participant's choice - 12 hours if triptan or ergot)


ParticipantsMigraine with or without aura (IHS 1988). History: 1 to 6 attacks/month in previous year

N = 312 (cross-over trial, 882 attacks)

M 59, F 253

Mean age 38 years

History of aura: 21%


InterventionsIbuprofen 400 mg, n = 212

ASA 2 x 500 mg, n = 222

Sumatriptan 50 mg, n = 226

Placebo, n = 222


OutcomesPain-free at 2 hours

Headache relief at 1 and 2 hours

Use of rescue medication

Presence of vomiting, photophobia, phonophobia

Adverse events

Withdrawals


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


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk"predetermined randomization code"

Allocation concealment (selection bias)Unclear riskNot described

Blinding (performance bias and detection bias)
All outcomes
Low risk"double-dummy" method with "matching placebo" for each treatment

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

Study sizeLow risk> 200 participants per treatment group


MethodsRandomised, double-blind, placebo-controlled, parallel-group. Single oral dose of ibuprofen with or without intravenous metoclopramide

Assessments at 0, 0.5 and 1 hour

If pain not controlled, participants asked to wait 1 hour before taking rescue medication


ParticipantsMigraine (predates, but consistent with IHS criteria), presenting at hospital emergency department

N = 40

No information on mean age, sex of population

Median baseline pain ≥ 8/10

History of aura: not reported


InterventionsIbuprofen 600 mg (oral) + placebo (IV), n = 10

Placebo (oral) + placebo (IV), n = 10

Ibuprofen 600 mg (oral) + metoclopramide 1 mg IV, n = 10

Placebo (oral) + metoclopramide 1 mg IV, n = 10


OutcomesUse of rescue medication at 1 hour


NotesOxford Quality Score: R1, DB2, W0. Total = 3


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot described

Allocation concealment (selection bias)Unclear riskNot described

Blinding (performance bias and detection bias)
All outcomes
Low risk"identically-appearing placebo"

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

Study sizeHigh risk< 50 participants per treatment group


MethodsMulticentre, randomised, double-blind (double-dummy), placebo-controlled, parallel-group. Single oral dose

Medication taken when migraine of moderate or severe intensity

Assessments at 0, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, and 4 hours

If pain not controlled, participants asked to wait 2 hours before taking rescue medication (of participant's choice)


ParticipantsMigraine with and without aura (IHS 1988). History: attack at least once every 2 months during past year. Untreated attacks ≥ moderate severity

N = 1559

M 306, F 1249

Mean age 38 years

History of aura: 21%


InterventionsIbuprofen 2 x 200 mg, n = 669

Paracetamol + aspirin + caffeine 2 x 250/250/65 mg, n = 669

Placebo, n = 221


OutcomesPain-free at 2 hours

Presence of nausea, vomiting, photophobia, phonophobia

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 (performance bias and detection bias)
All outcomes
Low riskDouble-dummy method

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

Study sizeLow risk> 200 participants per treatment group


MethodsMulticentre, randomised, double-blind, placebo-controlled, parallel-group. Single oral dose

Medication taken when migraine of moderate or severe intensity

Assessments at 0, 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, and 24 hours

Rescue medication allowed, but no details reported


ParticipantsMigraine with/without aura (IHS 1988). At least 12-month history of migraine with/without aura, average frequency of 0.5 to 8 attacks/month in the previous year. Untreated attacks ≥ moderate severity. Previous experience of some relief from OTC analgesics

Excluded participants with headaches that were usually severely disabling or incapacitating, or ≥ 20% accompanied by vomiting

N = 729

M 179, F 550

Mean age 37 years (35 participants were 12 to 19 years)

History of aura: 12%


InterventionsIbuprofen liquigel 200 mg, n = 198

Ibuprofen liquigel 400 mg, n = 191

Ibuprofen liquigel 600 mg, n = 198

Placebo, n = 142


OutcomesPain-free at 2 hours

Headache relief at 1 and 2 hours

24-hour sustained relief

Use of rescue medication

Presence of nausea, photophobia, phonophobia

Functional disability

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 (performance bias and detection bias)
All outcomes
Low risk"matching placebo"

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

Study sizeUnclear risk50 to 200 participants per treatment group


MethodsRandomised, double-blind, placebo-controlled, parallel-group. Single oral dose/attack (≥ 2 attacks treated)

Medication taken when migraine of moderate or severe intensity

Assessments at 0, 2, and 24 hours

If moderate or severe headache persisted after 2 hours, rescue medication allowed (sumatriptan 100 mg or piroxicam 20 mg)


ParticipantsMigraine with and without aura (IHS 1988). History: at least 12-month history of migraine with/without aura, no more than 6 attacks/month. Untreated attacks ≥ moderate severity

Excluded participants with headaches usually needing bedrest, or ≥ 20% accompanied by vomiting

N = 124 (101 analysed)

M 18, F 83

Mean age 32 years

History of aura: not reported


InterventionsIbuprofen 400 mg, n = 35

Rofecoxib 25 mg, n = 33

Placebo, n = 33


OutcomesHeadache relief at 2 hours

24-hour sustained relief

Use of rescue medication

Adverse events

Withdrawals


NotesOxford Quality Score: R2, DB1, W1. Total 4

Note exclusions >10% lost to follow-up

Note: headache relief not specifically defined


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk"random number tables"

Allocation concealment (selection bias)Unclear riskRandomisation done by one investigator and responses evaluated by the other, but no details about method of concealment

Blinding (performance bias and detection bias)
All outcomes
Unclear riskTablets had identical packets, but were not identical in appearance

Incomplete outcome data (attrition bias)
All outcomes
Unclear risk18.5% lost to follow-up without adequate explanation

Study sizeHigh risk< 50 participants per treatment group


MethodsRandomised, double-blind, placebo-controlled, parallel-group. Single oral dose/attack (≥ 2 attacks treated)

Medication taken when migraine of moderate or severe intensity

Assessments at 0, 2, and 24 hours

If moderate or severe headache persisted after 2 hours, rescue medication allowed (piroxicam 20 mg)


ParticipantsMigraine (IHS 1988). History: ≤ 8 attacks/month. Untreated attacks ≥ moderate severity

Excluded participants with headaches associated with recurrent vomiting

N = 155 analysed

M 59, F 106

Mean age 30 years

History of aura: not reported


InterventionsIbuprofen 400 mg, n = 52

Rizatriptan 10 mg, n = 53

Placebo, n = 50


OutcomesPain-free at 2 hours

Headache relief at 2 hours

24-hour sustained relief

Use of rescue medication

Adverse events

Withdrawals


NotesOxford Quality Score: R2, DB1, W1

Note: headache relief not specifically defined, and may be reduction from moderate or severe by two grades (Kalita 2009), which is not quite the same as reduction to mild or none


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk"computer-generated random numbers"

Allocation concealment (selection bias)Unclear riskRandomisation done by one investigator and responses evaluated by the other, but no details about method of concealment

Blinding (performance bias and detection bias)
All outcomes
Unclear riskMedication "provided in identical packets"

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

Study sizeUnclear risk50 to 200 participants per treatment group


MethodsDB, cross-over, double-dummy trial

Two centre, randomised, double-blind, placebo-controlled, cross-over. Single oral dose of each treatment for each of two migraine attacks - time between consecutive treated attacks not specified

Medication taken when pain was ≥ 60 mm

Assessments at 0, 0.25, 0.5, 0.75, 1, 2, 4, and 6 hours

If pain not controlled, participants asked to wait 2 hours before taking rescue medication


ParticipantsMigraine headache (IHS 1988). History: ≥ 2 months, without aura, 2 to 6 headache episodes/month

N = 34 (29 analysed for efficacy)

M 8, F 26

Mean age 34 years


InterventionsIbuprofen arginine 400 mg, n = 34

Placebo, n = 34


OutcomesHeadache relief at 1 and 2 hours

Use of rescue medication

Adverse events

Withdrawas


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


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot described

Allocation concealment (selection bias)Unclear riskNot described

Blinding (performance bias and detection bias)
All outcomes
Low risk"identical sachets"

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskCompleter analysis for efficacy, but adequate reasons given

Study sizeHigh risk< 50 participants per treatment group


MethodsMulticentre, randomised, double-blind, triple-dummy, placebo- and active-controlled, parallel-group. Single oral dose, and extension phase

Medication taken when migraine of moderate or severe intensity, and not resolving spontaneously.

Assessments at 0, 2, and 24 hours

If pain not controlled, participants asked to wait 2 hours before taking rescue medication


ParticipantsMigraine with and without aura (IHS 1988). History: 1 to 8 migraine attacks/month in the 6 months before enrolment

N = 783

M 108, F 675

Mean age 40 years

History of aura: 12%

32 participants took medication but were excluded from efficacy analyses - probably due to protocol violations or lack of post-baseline data.


InterventionsIbuprofen 400 mg, n = 199 (189 analysed for efficacy)

Rofecoxib 25 mg, n = 194 (187 analysed for efficacy)

Rofecoxib 50 mg, n = 196 (188 analysed for efficacy)

Placebo, n = 194 (187 analysed for efficacy)


OutcomesPain-free at 2 hours

Headache relief at 2 hours

Use of rescue medication

Presence of nausea, vomiting, photophobia, phonophobia

Functional disability

Adverse events

Withdrawals


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


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk"computer generated randomization schedule"

Allocation concealment (selection bias)Low riskRemote allocation

Blinding (performance bias and detection bias)
All outcomes
Low riskPlacebo tablets visually matched the three active treatments

Incomplete outcome data (attrition bias)
All outcomes
Unclear risk≤ 5% drop-outs in each group, with no reasons given

Study sizeUnclear risk50 to 200 participants per treatment group

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

Havanka 198933% of ibuprofen and 7% of placebo treatment arms had mild headaches

Kalita 2009Probably mostly the same population as in Misra 2007. Primary analysis according to presence or not of allodynic symptoms

Kloster 1992No usable data

Nebe 1995Mixed tension-type and migraine headaches

Pearce 1983No usable data

 
Comparison 1. Ibuprofen 200 mg versus placebo

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

 1 Pain-free at 2 hours2777Risk Ratio (M-H, Fixed, 95% CI)1.96 [1.36, 2.81]

 2 Headache relief at 2 hours2777Risk Ratio (M-H, Fixed, 95% CI)1.37 [1.17, 1.61]

 3 Headache relief at 1 hour2777Risk Ratio (M-H, Fixed, 95% CI)1.45 [1.15, 1.83]

 4 Any adverse event within 24 hours2780Risk Ratio (M-H, Fixed, 95% CI)0.85 [0.67, 1.08]

 5 Participants using rescue medication2777Risk Ratio (M-H, Fixed, 95% CI)0.70 [0.58, 0.86]

 6 Relief of associated symptoms at 2 h2Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

   6.1 Nausea
2429Risk Ratio (M-H, Fixed, 95% CI)1.33 [1.06, 1.67]

   6.2 Photophobia
2751Risk Ratio (M-H, Fixed, 95% CI)1.40 [1.05, 1.85]

   6.3 Phonophobia
2724Risk Ratio (M-H, Fixed, 95% CI)1.40 [1.08, 1.82]

 7 Relief of functional disability at 2 hours2757Risk Ratio (M-H, Fixed, 95% CI)1.40 [1.18, 1.66]

 
Comparison 2. Ibuprofen 400 mg versus placebo

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

 1 Pain-free at 2 hours62575Risk Ratio (M-H, Fixed, 95% CI)1.91 [1.60, 2.28]

 2 Headache relief at 2 hours71815Risk Ratio (M-H, Fixed, 95% CI)2.17 [1.92, 2.45]

   2.1 Standard formulation
51424Risk Ratio (M-H, Fixed, 95% CI)2.49 [2.12, 2.91]

   2.2 "Soluble" formulation
2391Risk Ratio (M-H, Fixed, 95% CI)1.59 [1.32, 1.92]

 3 Headache relief at 1 hour41269Risk Ratio (M-H, Fixed, 95% CI)1.89 [1.54, 2.30]

   3.1 Standard formulation
2878Risk Ratio (M-H, Fixed, 95% CI)1.75 [1.34, 2.27]

   3.2 "Soluble" formulation
2391Risk Ratio (M-H, Fixed, 95% CI)2.12 [1.55, 2.89]

 4 Sustained headache relief over 24 hours4879Risk Ratio (M-H, Fixed, 95% CI)2.17 [1.76, 2.69]

 5 Any adverse event within 24 hours72656Risk Ratio (M-H, Fixed, 95% CI)0.97 [0.82, 1.15]

 6 Specific adverse events7Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

   6.1 Nausea
72297Risk Ratio (M-H, Fixed, 95% CI)0.74 [0.54, 1.00]

   6.2 Abdominal pain
62230Risk Ratio (M-H, Fixed, 95% CI)2.36 [1.12, 4.96]

   6.3 Dizziness
31615Risk Ratio (M-H, Fixed, 95% CI)1.01 [0.46, 2.22]

   6.4 Somnolence
41717Risk Ratio (M-H, Fixed, 95% CI)2.53 [0.79, 8.17]

 7 Participants using rescue medication71815Risk Ratio (M-H, Fixed, 95% CI)0.67 [0.61, 0.74]

 8 Relief of associated symptoms at 2 h4Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

   8.1 Nausea
3634Risk Ratio (M-H, Fixed, 95% CI)1.54 [1.27, 1.86]

   8.2 Vomiting
293Risk Ratio (M-H, Fixed, 95% CI)1.53 [1.21, 1.92]

   8.3 Photophobia
41328Risk Ratio (M-H, Fixed, 95% CI)1.51 [1.29, 1.77]

   8.4 Phonophobia
41261Risk Ratio (M-H, Fixed, 95% CI)1.63 [1.39, 1.90]

 9 Relief of functional disability at 2 hours31114Risk Ratio (M-H, Fixed, 95% CI)1.61 [1.38, 1.89]

 
Comparison 3. Ibuprofen 400 mg versus rofecoxib 25 mg

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

 1 Headache relief at 2 hours2444Risk Ratio (M-H, Fixed, 95% CI)1.00 [0.85, 1.17]

 2 Sustained headache relief over 24 hours2444Risk Ratio (M-H, Fixed, 95% CI)0.85 [0.66, 1.10]

 3 Participants using rescue medication2444Risk Ratio (M-H, Fixed, 95% CI)1.15 [0.95, 1.38]

 
Comparison 4. Ibuprofen 600 mg versus placebo

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

 1 Pain-free at 2 hours1340Risk Ratio (M-H, Fixed, 95% CI)2.19 [1.37, 3.51]

 2 Headache relief at 2 hours1340Risk Ratio (M-H, Fixed, 95% CI)1.43 [1.19, 1.73]

 
Summary of findings for the main comparison.

Ibuprofen 400 mg compared with placebo for migraine headache

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

Settings: community

Intervention: ibuprofen 400 mg

Comparison: placebo

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

Pain free response at 2 h260 in 1000120 in 1000NNT 7.2 (5.9 to 9.2)6 studies, 2575 attacks, 529 eventsModerate1

Headache relief at 2 h250 in 1000570 in 1000NNT 3.2 (2.8 to 3.7)7 studies, 1815 attacks, 752 eventsModerate1

Sustained pain-free at 24 hno data

Sustained headache relief at 24 h190 in 1000450 in 1000NNT 4.0 (3.2 to 5.2)4 studies, 879 attacks, 288 eventsModerate1

At least one AE180 in 1000150 in 1000NNH 26 (15 to 100)8 studies, 2722 attacks, 441 eventsModerate1

Serious AEinsufficient data

CI: Confidence interval; NNT: number needed to treat; NNH: number needed to harm

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