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Three Part Question

In [children with migraines], which [analgesic] provides the most effective [symptomatic relief in an acute attack]?

Clinical Scenario

A 7-year-old boy is accompanied by his mother into ED. He is complaining of a moderate headache with nausea, and he appears pale and lethargic. You have ruled out meningitis and want to treat him for a migraine, but wonder which analgesic would be the most effective.

Search Strategy

Cochrane Library: (children OR paediatric OR adolescent):ti AND (migraine):ti,ab,kw AND (acute):ti,ab,kw AND (treatment OR management):ti,ab,kw

PubMed: ((((((((children[Title] OR paediatric[Title] OR adolescent[Title])) AND migraine) AND acute) AND (treatment OR management)))) AND "migraine disorders"[MeSH Terms]); Filters: English

Search Outcome

149 results were found, 6 of which directly relevant and of sufficient quality for inclusion.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Vasudevan et al. 2019 India	n=43 children (aged 6 to 12 years) with migraine without aura n=22 received oral paracetamol and n=21 received oral ibuprofen, at home, during an episode of acute migraine headache Pain‐freedom was defined as a score of zero in a 11‐point visual analogue pain scale (VAS), and pain‐relief was defined as >2‐point reduction from the baseline in the VAS	Single-blinded, randomised controlled trial (Level 1b)	Pain freedom 2 hours after drug intake	No significant difference between paracetamol and ibuprofen groups (32% vs 28% respectively, p=0.77)	Data extracted from abstract. Small sample size. Not double-blinded.
			Pain relief 2 hours after drug intake	No significant difference between paracetamol and ibuprofen groups (80% vs 80%, p=0.86)
			Side effects	No significant difference between paracetamol and ibuprofen with respect to drug side‐effects (13.6% vs 33.3% respectively, p=0.11)
Jeric et al. 2017 Croatia	n=201 (RCTs) and n=variable (SRs) children <18 years requiring treatment for an acute migraine attack	Meta-analysis of 3 RCTs and 10 systematic reviews (Level 1a)	Pain-free at 2hrs	RCTs: Ibuprofen was superior to placebo (OR = 3.96 (95% CI, 1.78 to 8.82)) No significant difference between paracetamol and placebo (p>0.05), or ibuprofen and paracetamol (p>0.05) SRs: Ibuprofen superior to placebo (OR = 3.96 (95% CI, 1.78 to 8.82); n=225) No significant difference between paracetamol and placebo ((95% CI, OR 0.66-4.13); n=84), or ibuprofen and paracetamol ((95% CI, OR 0.96-5.71); n=81)	RCTs: The age range of the children varied between the studies: 4-16 years in one, 6-12 years in the second, and 6-18 years in the third. All three trials had unclear or high risk of bias (using the Cochrane risk of bias tool). Different definitions of pain relief were used in each RCT. Different doses of analgesia were used in each RCT. For many outcomes, data was only available from one source. SRs: Conclusions about the efficacy of ibuprofen and paracetamol were discordant. The methodological quality of the majority of included SRs, judged by the AMSTAR tool, was low. Inability to separate data from primary studies for prepubertal and pubertal children.
			Pain relief at 2hrs	RCTs: Ibuprofen superior to placebo (OR = 3.58, p<0.001) No significant difference between paracetamol and placebo (p>0.05), or ibuprofen and paracetamol (p>0.05) SRs: Ibuprofen superior to placebo (OR = 3.58 (95% CI, 2.04 to 6.29); n=225) No significant difference between paracetamol and placebo ((95% CI, OR 0.82-4.67); n=84), or ibuprofen and paracetamol ((95% CI, OR 0.73-4.42); n=81)
			Number of patients with adverse events	No difference between the 3 groups (95% CI)
Richer et al. 2016 Canada	n=9158 children (<12 years) and adolescents (12-17 years) with migraine (+/- aura), requiring acute symptomatic treatment of a migraine attack, in which n=7630 received medication Pain freedom defined as the absence of pain at 2hrs before the use of additional or rescue medication Headache relief defined as a reduction in pain by 2 grades on a 5-point scale Triptans used included sumatriptan (n=10 studies), rizatriptan (n=4), zolmitriptan (n=4), almotriptan (n=1), eletriptan (n=1), naratriptan (n=1) Sumatriptan plus naproxen sodium doses used included: respectively, 10 mg + 60 mg, 30 mg + 180 mg, 85 mg + 500 mg	Meta-analysis of 27 RCTs (Level 1a)	Percentage of pain‐free participants at 2hrs	Children: Ibuprofen (RR 1.87, 95% CI 1.15 to 3.04; NNTB = 4) and triptans (RR 1.67, 95% CI 1.06 to 2.62) were superior to placebo Paracetamol (RR 1.40, 95% CI 0.75 to 2.58) and DHE were not superior to placebo Adolescents: Triptans ((RR 1.32, 95% CI 1.19 to 1.47), NNTB = 6) and sumatriptan plus naproxen sodium (p<0.05 for all doses) were superior to placebo No significant difference between ibuprofen and placebo (RR 7.00, 95% CI 0.99 to 49.69)	The overall quality of evidence provided by the review was moderate for the triptans, but low for paracetamol and ibuprofen, as they only identified a few studies.
			Percentage of participants with headache relief at 2hrs	Children: Ibuprofen superior to placebo No significant difference between paracetamol and placebo, nor DHE and placebo Adolescents: Ibuprofen (RR 2.50, 95% CI 1.02 to 6.10), triptans (RR 1.14, 95% CI 1.04 to 1.24), and sumatriptan and naproxen sodium (RR 3.25, 95% CI 1.78 to 5.94), NNTB = 6) were superior to placebo
			Percentage of participants taking rescue medication up to 6hrs after the test drug	Children: No significant difference between paracetamol and placebo, or ibuprofen and placebo Adolescents: Triptans (RR 0.79, 95% CI 0.72 to 0.87) and sumatriptan and naproxen sodium (RR 0.46, 95% CI 0.32 to 0.64) reduced use of rescue medication No significant difference between ibuprofen and placebo, nor DHE and placebo
			Percentage of participants who were initially pain-free or achieved headache relief within 2hrs without use of rescue medication, but experienced recurrence of any headache from 2-48hrs	Triptans reduced risk of headache recurrence (RR 0.79, 95% CI 0.68 to 0.93) No significant differences between other groups
			Percentage of participants with nausea at 2hrs after taking the test drug	No significant differences between groups
			Percentage of participants with vomiting within 2hrs of taking the test drug	No significant differences between groups
Richer et al. 2015 Canada	n=53 children (aged 5‐17) presenting with acute migraine to ED In addition to standard IV abortive therapy with metoclopramide (0.2 mg/kg; maximum 10 mg) and normal saline (10 ml/kg), n=27 received IV ketorolac (KET: 0.5 mg/kg; maximum 30 mg) and n=26 received placebo Follow‐up telephone interviews were conducted 24 hours after ED discharge	Double-blinded, two-centre, randomised controlled trial (Level 1b)	Difference in pain intensity between baseline and discharge	No significant difference between KET and placebo (-42 vs -38 respectively; pain score difference of p=3.97, 95% CI: ‐16.5 to 8.5)	Data extracted from abstract. Small sample size.
			Rate of relapse	No significant difference between KET and placebo groups
			Side effects	No significant difference between KET and placebo groups
Gallelli et al. 2013 Italy	n=80 children aged 5-16 years with at least 4 attacks/month of primary migraine Assigned in 2 groups to receive treatment with paracetamol or ibuprofen Assigned to receive at pain onset: paracetamol (PO 15 mg/kg, n=40) or ibuprofen (PO 10 mg/kg, n=40) A visual analogue scale was used to evaluate pain intensity	Single-blinded, single-centre trial (Level 2b)	Time taken for decrease in acute pain	Significantly faster with ibuprofen (mean 31.95 +/- 1.7 mins) than with paracetamol (mean 48.5 +/-5.16 mins) (p=0.004; 95% CI, -27.54 to-5.54; t=-3.045)	No mention of randomisation.
Reiter et al. 2005 USA	n=31 children who received IV valproic acid (VPA) for acute migraine attack over an 18 month period Most children were considered to have failed some form of conventional migraine therapy prior to the VPA infusion Efficacy was measured using a 10‐point numerical pain scale Most children received a fixed VPA regimen consisting of 1000mg (first dose) infused at 50mg/min. If pain reduction was not sufficient, a second VPA dose of 500mg was provided	Retrospective observational study (Level 2b)	Reduction in pain score from baseline (by end of clinic visit)	In children requiring only 1 dose: average = 39.8% reduction In children requiring 2 doses: average = 57.1% reduction	Data taken from 48 visits from 31 children, so representation was not equal between children. By its nature, this trial mostly included children with migraines severe enough to be resistant to conventional pain relief. Most children required concomitant IV dexamethasone and/or ondansetron to help alleviate symptoms of nausea and vomiting associated with migraine pain and/or VPA therapy, so unable to assess effect of drug on these symptoms.
			Proportion of patients with major improvement (51-80% reduction) in or complete relief (81-100% reduction) of headache pain	46.8% of all patients

Comment(s)

Paediatric migraine headaches are common, affecting around 3-10% of children. With a range of medication available off the shelves, it can be difficult for parents to know how best to manage acute episodes at home. Importantly, some parents may be unaware of the dangers of using aspirin in children under 16 years. Current guidelines suggest the use of simple analgesia (NSAID or paracetamol) as first-line medication, with escalation to a nasal triptan if ineffective. In this review we have analysed the results of 2 meta-analyses and 4 original research studies. The emphasis in an acute migraine treatment plan should be on providing pain relief, reducing associated disability, and minimising drug side effects. With regards to first-line analgesics, ibuprofen was superior at providing complete or partial pain relief in children and had a faster onset of action than paracetamol. There is insufficient evidence in favour of paracetamol. For children and adolescents, triptans appear to be effective in providing pain relief. Sumatriptan was the preferred drug in this class. Triptans also reduced the risk of headache recurrence but were associated with an increased number of minor adverse side effects; in the case of intranasal triptans, this included taste disturbance, nasal symptoms, and nausea. Triptans should be made available in situations where ibuprofen has failed to provide symptomatic relief. There were no significant differences in the ability of these 3 drugs to reduce symptoms of nausea and vomiting. In comparison, IV valproic acid infusions had a delayed time to maximal effectiveness, and patients often required two sets of infusions to give sufficient pain relief. IV ketorolac was found to be ineffective. Going forward, more double-blinded, randomised-controlled trials are warranted to stratify optimal treatments by age (i.e. adolescents vs. children), and more head-to-head comparisons of simple analgesics (paracetamol, NSAIDs) are necessary. The combination of sumatriptan plus naproxen sodium should be considered in future trials.

Clinical Bottom Line

Ibuprofen is the most effective, quick-acting, and accessible first-line analgesic, with consistent pain relief shown across studies. Paracetamol should be considered if ibuprofen is contraindicated. Triptans are not only effective for symptomatic relief, but reduce the risk of headache recurrence and use of rescue relief. However, tolerance may be an issue as they are associated with more side effects, and only nasal preparations are approved for children <18 years. Other types of medication are available, which should be considered in refractory cases.

References

1. Vasudevan, P., Mishra, D. and Juneja, M. Paracetamol versus Ibuprofen for the acute treatment of migraine headache in children. Headache: The Journal of Head and Face Pain 2019; 59, p.75
2. Jeric, M., Surjan, N., Jelicic Kadic, A., Riva, N. and Puljak, L. Treatment of acute migraine attacks in children with analgesics on the World Health Organization Essential Medicines List: A systematic review and GRADE evidence synthesis. Cephalalgia 2017; 38(9), pp.1592-1607
3. Richer, L., Billinghurst, L., Linsdell, M., Russell, K., Vandermeer, B., Crumley, E., Durec, T., Klassen, T. and Hartling, L. Drugs for the acute treatment of migraine in children and adolescents. Cochrane Database of Systematic Reviews. Cochrane Database Syst Rev. 2016; 4(4)
4. Richer, L., Ali, S., Rosychuk, R., Newton, A., Rowe, B. and Johnson, D. Randomized controlled trial of ketorolac in combination with metoclopramide for the treatment of children with migraine in the emergency department. CEJM 2015; 17(S2), p.S8
5. Gallelli, L., Avenoso, T., Falcone, D., Palleria, C., Peltrone, F., Esposito, M., De Sarro, G., Carotenuto, M. and Guidetti, V. Effects of Acetaminophen and Ibuprofen in Children With Migraine Receiving Preventive Treatment With Magnesium. Headache: The Journal of Head and Face Pain 2013, 54(2), pp.313-324
6. Reiter, P., Nickisch, J. and Merritt, G. Efficacy and Tolerability of Intravenous Valproic Acid in Acute Adolescent Migraine. Headache: The Journal of Head and Face Pain 2005; 45(7), pp.899-903