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Paracetamol (acetaminophen) with or without an antiemetic for acute migraine headaches in adults

  1. Sheena Derry*,
  2. R Andrew Moore

Editorial Group: Cochrane Pain, Palliative and Supportive Care Group

Published Online: 30 APR 2013

DOI: 10.1002/14651858.CD008040.pub3


How to Cite

Derry S, Moore RA. Paracetamol (acetaminophen) with or without an antiemetic for acute migraine headaches in adults. Cochrane Database of Systematic Reviews 2013, Issue 4. Art. No.: CD008040. DOI: 10.1002/14651858.CD008040.pub3.

Author Information

  1. 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]

MethodsR, DB, PC, parallel-group

Four attacks treated. Medication (2 tablets) taken at onset of attack, repeated after 1 and 4 h if necessary (maximum 6 tablets in 24 h). Rescue medication (aspirin 600 mg) after 4 h if necessary


ParticipantsCommon or classical migraine (≥ 2 years). Aged 20-50 years. Frequency 2 to 8 per month. Excluded: prophylactic treatment within 4 weeks

N = 49 (42 completed 4 attacks)

M 16, F 33

Mean age 33 years


InterventionsParacetamol + metoclopramide 2 x 500/5 mg

Placebo


OutcomesSeverity and duration of attacks

Adverse events

Withdrawals


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

Predates IHS diagnostic criteria


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"matched placebo"

Incomplete outcome data (attrition bias)
All outcomes
High riskCompleter analysis

Study sizeHigh risk< 50 participants per treatment group


MethodsR, DB, DD, AC, cross-over

Two attacks treated with single doses of each of two study medications. Medication taken when pain was moderate or severe. Rescue medication after 4 h if necessary

Severity assessed at 0, 1, 2, 4, 24, 48, 72 h


ParticipantsMigraine ± aura (diagnostic criteria not reported). Aged 18 to 65 years. Duration of condition > 1 year. Frequency ≥ 2 every 12 weeks. Prophylactic therapy (pizotifen, clonidine, β-blockers, calcium channel blockers) allowed if stable for ≥ 3 months and kept constant

N = 161 (120 took both treatments and were analysed for efficacy)

M 9, F 111

Mean age 43 years


InterventionsParacetamol + domperidone 1000/20 mg + placebo

Sumatriptan 50 mg + placebo


OutcomesHeadache relief at 2 h

Presence of nausea and vomiting

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 placebos"

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskEfficacy data analysed for participants taking both interventions. Safety data included all participants taking any intervention

Study sizeUnclear risk50 to 200 participants per treatment group


MethodsMulticentre, R, DD, AC and PC, parallel-group

Single attack treated with a single dose of study medication. Medication taken when pain was moderate or severe. Rescue medication after 2 h if necessary

Assessments at 0, 0.5, 1, 1.5, 2, 3, 4, 24 h


ParticipantsMigraine ± aura (IHS 2004). Aged ≥ 18 years. Frequency 0.5 to 6 per month. Untreated severity ≥ moderate. Excluded: >10 headache days per month or used analgesics regularly > 3 days per week

N = 173

M 21, F 152

Mean age 43 years


InterventionsParacetamol 1000 mg, n = 43

Rizatriptan 10 mg, n = 43

Rizatriptan + paracetamol 10/1000 mg, n = 48

Placebo, n = 39


OutcomesPain-free at 2 h

Headache relief at 2 h

24 h sustained relief

24 h sustained pain-free

Relief of nausea, photophobia, phonophobia, functional disability

Use of rescue medication

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"

Allocation concealment (selection bias)Unclear riskNot described

Blinding (performance bias and detection bias)
All outcomes
Low riskDouble-dummy, "matched placebos"

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

Study sizeHigh risk< 50 participants per treatment group


MethodsMulticentre, R, DB, parallel-group

Three attacks treated with same medication. Second dose of sumatriptan or placebo paracetamol + domperidone allowed after 2 h if necessary. Rescue medication after 4 hours if necessary


ParticipantsMigraine ± aura (diagnostic criteria not reported). Aged 20 to 65 years. Duration of condition > 1 year. Frequency ≥ 1 every 8 weeks. Excluded: prophylactic treatment within 2 weeks, IHD, chronic analgesic use for other condition

N = 607

M 98, F 509

Mean age 39 years


InterventionsParacetamol + metoclopramide 1000/10 mg, n = 302

Sumatriptan 100 mg, n = 305


OutcomesHeadache relief at 2 h

24 h sustained relief

Relief of nausea, vomiting, photophobia/phonophobia

Use of rescue medication

Adverse events

Withdrawals


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


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskComputer-generated

Allocation concealment (selection bias)Low riskInvestigators provided with a sealed envelope for each patient - to be returned unopened at the end of the trial, or patient discontinued from trial

Blinding (performance bias and detection bias)
All outcomes
Low riskEach active treatment had a matched placebo tablet (triple dummy)

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

Study sizeLow risk> 200 participants per treatment group


MethodsMulticentre, R, DB, parallel-group

Three attacks treated with single doses of the same medication. Rescue medication after 4 hours if necessary


ParticipantsMigraine ± aura (diagnostic criteria not reported). Aged 20 to 65 years. Duration of condition > 1 year. Frequency ≥ 1 every 8 weeks. Excluded: prophylactic treatment within 2 weeks, IHD, chronic analgesic use for other condition

N = 721

M 124, F 597

Mean age 40 years


InterventionsParacetamol + metoclopramide 1000/10 mg, n = 373

Sumatriptan 100 mg, n = 348


OutcomesHeadache relief at 2 h

24 h sustained relief

Relief of photophobia/phonophobia

Use of rescue medication

Adverse events

Withdrawals


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


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskComputer-generated

Allocation concealment (selection bias)Low riskInvestigators provided with a sealed envelope for each patient - to be returned unopened at the end of the trial, or patient discontinued from trial

Blinding (performance bias and detection bias)
All outcomes
Low riskEach active treatment had a matched placebo tablet (triple dummy)

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

Study sizeLow risk> 200 participants per treatment group


MethodsMulticentre, R, DB, PC and AC, four-way cross-over

Four consecutive attacks treated with single doses of each test medication


Participants"Simple" migraine (criteria of Soyka). Aged 18-70 years (included one patient aged 75 years). Prior attacks uniform with regard to headache intensity and duration

N = 288 (completed 4 attacks)

M 55, F 233

Mean age 42 years


InterventionsParacetamol 1000 mg

Dihydroergotamine 2 mg

Paracetamol + dihydroergotamine 1000/2 mg

Placebo


OutcomesPain-free at 2 h

Headache relief at 1 h and 2 h

≤ 50% pain relief at 1 h and 2 h

Presence of nausea, vomiting, photophobia, phonophobia

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 risk"randomised order in the form of a Latin square"

Allocation concealment (selection bias)Unclear riskNot described

Blinding (performance bias and detection bias)
All outcomes
Unclear riskNot described

Incomplete outcome data (attrition bias)
All outcomes
High riskCompleter analysis

Study sizeLow risk> 200 participants per treatment group


MethodsMulticentre, R, DB, PC, parallel-group

Single attack treated with a single dose of study medication. Medication taken when pain was moderate or severe. Rescue medication after 2 h if necessary

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


ParticipantsMigraine ± aura (IHS 1988). Aged ≥ 18 years. Frequency 0.5 to 6 per month. Untreated severity ≥ moderate. Excluded: require bedrest for >50%, or vomiting with >2 0% of attacks

N = 289

M 58, F 231

Mean age 37 years

15% with aura


InterventionsParacetamol 1000 mg, n = 147

Placebo, n = 142


OutcomesPain-free at 2 h

Headache relief at 1 h and 2 h

Relief of nausea, photophobia, phonophobia, functional disability

Use of rescue medication

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 schedule"

Allocation concealment (selection bias)Low risk"all information kept in a blinded form until after database was locked"

Blinding (performance bias and detection bias)
All outcomes
Low risk"identical appearing placebo tablets"

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

Study sizeUnclear risk50 to 200 participants per treatment group


MethodsR, DB, PC, cross-over

Three attacks treated, each with a single dose of each of three study medications. Medication taken at onset of attack, repeated every 4 h (maximum four doses). Rescue medication after 1 h if necessary

Severity assessed at 0, 0.5, 1, 2, 4, 8, 24 h


ParticipantsMigraine ± aura (IHS 1988). Aged 18 to 70 years

N = 58

M 8, F 50

Median age 43 years

Aura: 43%


InterventionsParacetamol + domperidone 1000/20 mg, n = 44

Paracetamol + domperidone 1000/30 mg, n = 46

Paracetamol 1000 mg + placebo, n = 44


OutcomesUse of rescue medication

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"predetermined randomized code"

Allocation concealment (selection bias)Unclear riskNot described

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

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

Study sizeHigh risk< 50 participants per treatment group


MethodsR, DB, AC, cross-over

Two attacks treated, each with a single dose of each study medication. Mediaction taken at onset. Rescue medication (usual) after 3 h if necessary


ParticipantsMigraine (ad hoc criteria). Aged 18 to 70 years. Frequency 1 to 6 attacks per month

N = 149 (116 used both treatments)

M 16, F 100

Mean age 45 years


InterventionsParacetamol 1000 mg, n = 116

Tolfenamic acid 400 mg, n = 116


OutcomesAdverse events


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 sealed packages containing two capsules of each drug"

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskCompleter analysis (treating both attacks), but adequate reasons for exclusion given for all others

Study sizeUnclear risk50 to 200 participants per treatment group


MethodsR, DB, AC, cross-over

Three attacks treated, each with a single dose of each study medication. Mediaction taken when pain moderate or severe. Rescue medication (usual) if no relief within 4 h or recurrence

Pain intensity assessed at 1, 2, 4, 24 h


ParticipantsMigraine (ICHD-II criteria). Aged 18 to 65 years. Frequency 1 to 8 attacks per month

N = 173 (1047 attacks, 118 participants used all three treatments)

M 23%, F 77%

Mean age 34 years


InterventionsParacetamol 1000 mg, n = 350 attacks evaluated
Etodolac 400 mg, n = 339 attacks evaluated
Etodolac 800 mg, n = 358 attacks evaluated


OutcomesPain-free at 2 h

Headache relief at 1 h and 2 h

24-h sustained pain-free

Adverse events


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"Treatment drugs were dispensed as 2 pills of similar coating to keep the blindness"

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskDrop-outs not adequately accounted for - possibly lack of qualifying headache

Study sizeLow risk> 200 attacks per treatment group


MethodsMulticentre, R, DB, PC, parallel-group

Single attack treated with a single dose of study medication. Medication taken when pain was moderate or severe. Rescue medication after 2 h if necessary

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


ParticipantsEpisodic migraine ± aura (IHS 2004). Age ≥ 18 years. History of 0.5 to 6 attacks/month in past year and previous treatment with OTC medication. Untreated severity ≥ moderate. Excluded: require bedrest for > 50%, or vomiting with > 20% of attacks

N = 346

M 58, F 288

Mean age 39 years

22% with aura


InterventionsParacetamol 1000 mg, n = 177

Placebo, n = 169

Prophylactic medication continued unchanged


OutcomesPain-free at 2 h

Headache relief at 1 h and 2 h

Relief of nausea, photophobia, phonophobia, functional disability

Use of rescue medication

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"blister cards with winged 2-piece code label including treatment assignment according to sponsor-generated randomization code"

Blinding (performance bias and detection bias)
All outcomes
Low risk"tablets identical in shape, size and color"

Incomplete outcome data (attrition bias)
All outcomes
Low riskAdequate reasons for exclusion given for all others.

Study sizeUnclear risk50 to 200 participants per treatment group

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

Diamond 1976No usable single dose data. No diagnostic criteria.

Diener 2005Mixed migraine and tension headache.

Larsen 1990Up to 8 attacks treated/participant, but total number of attacks/treatments not reported, so denominator unknown.

 
Comparison 1. Paracetamol 1000 mg versus placebo

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

 1 Pain-free at 2 hours4Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

   1.1 Moderate/severe pain
3717Risk Ratio (M-H, Fixed, 95% CI)1.80 [1.24, 2.62]

   1.2 Onset of attack
1576Risk Ratio (M-H, Fixed, 95% CI)1.37 [1.04, 1.80]

 2 Headache relief at 1 hour2Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

   2.1 Moderate/severe pain
2635Risk Ratio (M-H, Fixed, 95% CI)1.97 [1.52, 2.55]

 3 Headache relief at 2 hours4Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

   3.1 Moderate/severe pain
3717Risk Ratio (M-H, Fixed, 95% CI)1.55 [1.32, 1.83]

   3.2 Onset of attack
1576Risk Ratio (M-H, Fixed, 95% CI)1.95 [1.47, 2.57]

 4 Any adverse event41293Risk Ratio (M-H, Fixed, 95% CI)0.78 [0.64, 0.95]

 5 Use of rescue medication at 6 h2635Risk Ratio (M-H, Fixed, 95% CI)0.59 [0.47, 0.74]

 6 Relief of associated symptoms at 2 hours3Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

   6.1 Nausea
2536Risk Ratio (M-H, Fixed, 95% CI)1.37 [1.17, 1.61]

   6.2 Photophobia
3985Risk Ratio (M-H, Fixed, 95% CI)1.40 [1.19, 1.64]

   6.3 Phonophobia
3944Risk Ratio (M-H, Fixed, 95% CI)1.42 [1.21, 1.67]

 7 Relief of functional disability at 2 hours2610Risk Ratio (M-H, Fixed, 95% CI)1.76 [1.24, 2.48]

 
Comparison 2. Paracetamol 1000 mg plus metoclopramide 10 mg versus sumatriptan 100 mg

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

 1 Headache relief at 2 hours21140Risk Ratio (M-H, Fixed, 95% CI)0.93 [0.81, 1.07]

 2 Any adverse event21328Risk Ratio (M-H, Fixed, 95% CI)0.61 [0.53, 0.71]

 3 Major adverse event21328Risk Ratio (M-H, Fixed, 95% CI)0.50 [0.30, 0.83]

 4 Use of rescue medication at 24 h21243Risk Ratio (M-H, Fixed, 95% CI)1.17 [1.01, 1.36]

 5 Relief of light/noise sensitivity at 2 hours21001Risk Ratio (M-H, Fixed, 95% CI)1.01 [0.85, 1.21]

 
Summary of findings for the main comparison.

Paracetamol 1000 mg compared with placebo for migraine headache

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

Settings: community

Intervention: paracetamol 1000 mg

Comparison: placebo

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

Pain free response at 2 h190 in 1000100 in 1000NNT 12 (7.5 to 32)3 studies, 717 attacks, 104 eventsLow1

Headache relief at 2 h560 in 1000360 in 1000NNT 5.0 (3.7 to 7.7)3 studies, 717 attacks, 334 eventsLow1

Headache relief at 1 h390 in 1000200 in 1000NNT 5.2 (3.8 to 8.1)2 studies, 655 attacks, 189 ventsLow1

At least one AE180 in 1000230 in 1000NNH 21 (11 to 300)4 studies, 1293 attacks, 261 eventsLow1

Sustained pain-free at 24 hno data

Sustained headache relief at 24 hno data

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