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

  1. Sheena Derry1,*,
  2. Roy Rabbie2,
  3. R Andrew Moore1

Editorial Group: Cochrane Pain, Palliative and Supportive Care Group

Published Online: 30 APR 2013

Assessed as up-to-date: 5 MAR 2013

DOI: 10.1002/14651858.CD008783.pub3


How to Cite

Derry S, Rabbie R, Moore RA. Diclofenac with or without an antiemetic for acute migraine headaches in adults. Cochrane Database of Systematic Reviews 2013, Issue 4. Art. No.: CD008783. DOI: 10.1002/14651858.CD008783.pub3.

Author Information

  1. 1

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

  2. 2

    Epsom and St Helier University Hospitals NHS Trust, Department of Respiratory Medicine, London, 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: Edited (no change to conclusions)
  2. Published Online: 30 APR 2013

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Characteristics of included studies [ordered by study ID]
Dahlof 1993

MethodsMulticentre, randomised, double-dummy, placebo-controlled, 3-period, cross-over study

Single oral dose of each treatment for each of three consecutive attacks, with a minimum of 3 days between successively treated attacks. Medication to be taken at the earliest sign of a migraine attack (onset aura/headache)

Assessments at 0.5, 1, 1.5, and 3 hours

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


ParticipantsMigraine with or without aura (IHS 1988). History: 2 to 8 migraine attacks/month

Exclusions: participants with contraindication to study medication, concomitant NSAID therapy, ergotamine/analgesic addiction, pregnancy or inadequate contraception

N = 72

M: 16, F: 56

Mean age 40 years, range 18 to 61

Migraine with aura 58%


InterventionsDiclofenac-K 50 mg tablet, n = 64

Diclofenac-K 100 mg tablet, n = 64

Placebo, n = 64

All prophylaxis stopped ≥ 2 weeks before start of study


OutcomesHeadache relief (100 mm VAS and 4-point scale) at 2 hours

Associated symptoms

Working ability

Use of rescue medication

Adverse events

Withdrawals


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)Low riskMedication supplied in packs with sequential patient number. Patient allocated lowest available number

Blinding (performance bias and detection bias)
All outcomes
Low riskTablets "of identical outward appearance and shape"

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskDenominator in graphs unclear

SizeUnclear riskGroup size 50 to 200

Diener 2006

MethodsMulticentre, randomised, double-blind, double-dummy, placebo-controlled, cross-over trial

Single dose of each treatment for each of three separate migraine attacks, with at least 48 hours between attacks. Medication taken at the first sign of a migraine attack

Assessments at 0, 15, 30, 45, 60, and 90 minutes and 2, 3, 4, 6, and 8 hours

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


ParticipantsMigraine with or without aura (IHS 1988). History: 2 to 6 migraine attacks/month in previous 3 months

Exclusions: participants with interval headaches between attacks, other types of migraine, pregnancy or lactation or inadequate contraception, known hypersensitivity to study or related medications, significant systemic disease

N = 317

M: 44, F: 273

Mean age: 39 years


InterventionsDiclofenac-K sachet 50 mg, n = 291

Diclofenac-K tablet 50 mg, n = 298

Placebo, n = 299

Prophylactic treatment allowed with a single agent if stable


OutcomesHeadache relief at 1, 2 hours

Pain-free at 2 hours

Sustained headache relief at 24 hours

Sustained pain-free at 24 hours

Use of rescue medication

Relief from accompanying symptoms (combined outcome)

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)Low riskRemote allocation

Blinding (performance bias and detection bias)
All outcomes
Low risk"Double dummy"

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

SizeLow riskGroup size > 200

DKSMSG 1999

MethodsMulticentre, randomised, double-blind, double-dummy, placebo- and active-controlled, cross-over trial

Single oral dose of each medication to treat each of 4 separate attacks; each patient was to receive all 4 treatments during the course of the trial. Medication taken at first sign of pain and attacks separated by ≥ 48 hours

Assessments at 20 minutes, 40 minutes, and 1, 1.5, 2, 3, 4, 6 and 8 hours

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


ParticipantsMigraine ± aura (IHS 1988). History: 2 to 6 attacks/month in previous 6 months

Exclusions: participants experiencing non-migrainous interval headaches or other types of migraine

N = 156

M: 37, F: 119

Median age 33 years, range 19 to 70 years

Median time since first diagnosis 15 years


InterventionsDiclofenac-K 50 mg, n = 115

Diclofenac-K 100 mg, n = 115

Sumatriptan 100 mg, n = 115

Placebo, n = 115

Beta-blockers allowed if dose stable


OutcomesPain intensity (100 mm VAS) at 2 hours - group mean data

Associated symptoms

Working ability

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 (performance bias and detection bias)
All outcomes
Low risk"Double dummy"

Incomplete outcome data (attrition bias)
All outcomes
Low riskDrop-outs described. Completer analysis for efficacy, but did not contribute to efficacy analyses. Safety analysis on all participants receiving treatment.

SizeUnclear riskGroup size 50 to 200

Lipton 2010

MethodsMulticentre, randomised, double-blind, double-dummy, placebo-controlled, parallel-group, single-attack trial

Single dose of each medication to treat a single migraine attack, with at least 48 hours of treating previous migraine. Trial medication was to be taken at the earliest sign of a migraine attack, when migraine of moderate or severe intensity

Assessments at 0, 15, 30 and 45 minutes and 1, 1.5, 2, 2.5, 3, 4, 8, 16 and 24 hours

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


ParticipantsMigraine with or without aura (IHS 2004). History: at least one migraine attack/month in previous year

Exclusions: participants experiencing vomiting in 20% of attacks or needing bed rest with most attacks, pregnancy, lactation or inadequate contraception, hypersensitivity to study or related medication, traumatic injury to head or neck within 6 months, other significant medical history

N = 690 (ITT population)

M: 105, F: 585

Mean age: 40 years, range: 18 to 65

Migraine with aura 13%


InterventionsDiclofenac-K oral solution 50mg, n = 343

Placebo, n = 347

Prophylactic treatment allowed if dose stable for ≥ 3 months


OutcomesHeadache relief at 2 hours

Pain-free at 2 hours

Sustained pain-free at 24 hours

Associated symptoms

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 riskBoth treatments made up to clear solution

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

SizeLow riskGroup size > 200

Vecsei 2007

MethodsMulticentre, randomised, double-blind, placebo-controlled, cross-over trial

Single oral dose of each treatment for four consecutive migraine attacks, with at least 48 hours between consecutive treatments

Medication to be taken at the earliest sign of migraine attack, and a second tablet could be taken 1 hour later if relief was judged insufficient by the participant

Assessments at 0, 2 and 24 hours

"In the case of a migraine attack recurring within 48 hours, the patient was allowed to treat this attack with his 'usually used attack medicine' ('rescue medication')"


ParticipantsMigraine without aura. History: 1 to 6 migraine attacks/month in the 12 months prior to enrolment

Exclusions: participants usually experiencing severe attacks, known hypersensitivity to study medication, concomitant treatment with drugs that interact with diclofenac, serious psychiatric disease, drug abuse headache

N = 133 (ITT participants)

M: 14, F: 119

Mean age 42 years


InterventionsDiclofenac epolamine (DHEP) 65 mg sachet, n = 133

Placebo, n = 133 


OutcomesHeadache relief at 2 hours

"Pain-free" at 2 hours

Use of "rescue medication" (appears to refer to medication taken to treat recurrence - see 'Methods', above)

Working ability

Associated symptoms

Adverse events


NotesOxford Quality Score: R2, DB1, W0. Total = 3


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk"Computer-generated using validated software"

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
Unclear riskData missing for 22/155 participants without adequate reason

SizeUnclear riskGroup size 50 to 200

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

Bigal 2002Intramuscular administration of diclofenac

Comoglu 2011Mixed baseline pain (some mild) with results not reported separately

Del Bene 1987Intramuscular administration of diclofenac

Karachalios 1992Intramuscular administration of diclofenac

Massiou 1991Diagnostic criteria not specified. Baseline pain not specified

Peroutka 200430% of participants unaccounted for in first period of cross-over

 
Characteristics of studies awaiting assessment [ordered by study ID]
Novartis 1995

MethodsRansomised, double-blind, active-control, cross-over

Single dose, with additional tablets as needed after 2 hours (maximum 3 per attack for diclofenac or 6 per attack for Cafergot)

ParticipantsN = 63 (completed both phases?)

InterventionsDiclofenac potassium (Cataflam) 50 mg

Cafergot (ergotamine 1 mg + caffeine 100 mg)

Outcomes

NotesReferenced in McNeely 1999 as follows: Data on file: GP 45 840 12, Cataflam tablets, diclofenac-K. Novartis Pharma AG (Basel); 1995

Novartis 1998

MethodsRandomised, double-dummy, placebo- and active-control, parallel-group

Single dose, with additional tablets as needed after 2 hours (maximum 4 per attack for diclofenac or 5 per attack for Cafergot)

ParticipantsMigraine ± aura. Mean baseline pain 50/100 mm

N = 423

InterventionsDiclofenac potassium 50 mg, n = 140 (evaluable population)

Cafergot (ergotamine 1 mg + caffeine 100 mg), n = 144

Placebo, n = 146

Outcomes

NotesReferenced in McNeely 1999 as follows: Data on file: Novartis Pharma AG (Basel). 604man.doc/final draft; 1998

 
Comparison 1. Diclofenac 50 mg versus placebo

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

 1 Pain-free at 2 hours21477Risk Ratio (M-H, Fixed, 95% CI)2.02 [1.57, 2.61]

    1.1 Standard tablet
1394Risk Ratio (M-H, Fixed, 95% CI)1.37 [0.81, 2.33]

    1.2 Soluble
21083Risk Ratio (M-H, Fixed, 95% CI)2.27 [1.69, 3.05]

 2 Headache relief at 2 hours21477Risk Ratio (M-H, Fixed, 95% CI)1.47 [1.31, 1.65]

    2.1 Standard tablet
1394Risk Ratio (M-H, Fixed, 95% CI)1.31 [1.01, 1.71]

    2.2 Soluble
21083Risk Ratio (M-H, Fixed, 95% CI)1.52 [1.34, 1.73]

 3 Sustained pain-free at 24 hours21578Risk Ratio (M-H, Fixed, 95% CI)2.25 [1.68, 3.01]

    3.1 Standard tablet
1447Risk Ratio (M-H, Fixed, 95% CI)1.61 [0.91, 2.83]

    3.2 Soluble
21131Risk Ratio (M-H, Fixed, 95% CI)2.53 [1.80, 3.55]

 4 Relief of functional disability2873Risk Ratio (M-H, Fixed, 95% CI)2.36 [1.80, 3.08]

 5 Any adverse events21075Risk Ratio (M-H, Fixed, 95% CI)1.11 [0.86, 1.45]

 
Summary of findings for the main comparison.

Diclofenac compared with placebo for migraine headache

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

Settings: community

Intervention: diclofenac 50 mg

Comparison: placebo

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

Pain-free at 2 h220 in 1000110 in 1000NNT 8.9 (6.7 to 13)2 studies, 1447 participants

262 events
Moderate1Potassium salt; standard tablet and soluble formulations

Headache relief at 2 h550 in 1000390 in 1000NNT 6.2 (4.7 to 9.1)2 studies, 1447 participants

718 events
Moderate1Potassium salt; standard tablet and soluble formulations

Sustained pain-free at 24 h190 in 100082 in 1000NNT 9.5 (7.2 to 14)2 studies, 1578 participants, 228 events2Moderate1Potassium salt; standard tablet and soluble formulations

Sustained headache relief at 24 hNo data

At least one AE180 in 1000160 in 1000RR 1.1 (0.86 to 1.6)3 studies, 1075 participants, 187 eventsLow1Potassium salt; standard tablet and soluble formulations

Serious AENo eventsNo events

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

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 - includes a small proportion of participants with mild pain at baseline