Treatment of acute migraine attacks in children with analgesics on the World Health Organization Essential Medicines List: A systematic review and GRADE evidence synthesis

Abstract

Background

The World Health Organization Essential Medicines List (WHO EML) contains two analgesics for treatment of acute migraine attacks in children, ibuprofen and paracetamol.

Methods

The Embase, CDSR, CENTRAL, DARE and MEDLINE databases were searched up to 18 April 2017. We analyzed randomized controlled trials (RCTs) and systematic reviews (SRs) that investigate the efficacy and safety of ibuprofen or paracetamol for treatment of acute migraine attacks in children. We conducted meta-analysis and assessments of evidence with GRADE, Cochrane risk of bias tool, and AMSTAR.

Results

Three RCTs (201 children) and 10 SRs on ibuprofen and/or paracetamol for acute migraine attacks in children were included. Meta-analysis indicated that ibuprofen was superior to placebo for pain-free at 2 h or pain relief at 2 h, without difference in adverse events. There were no differences between paracetamol and placebo, or ibuprofen and paracetamol. Ten SRs that analyzed various therapies for migraine in children were published between 2004 and 2016, with discordant conclusions.

Conclusion

Limited data from poor quality RCTs indicate that ibuprofen and paracetamol might be effective analgesics for treating migraine attacks in children. Inclusion of ibuprofen and paracetamol as antimigraine medicines for children in the WHO EML is supported by indirect evidence from studies in adults.

Keywords

Ibuprofen paracetamol migraine children World Health Organization Essential Medicines List Protocol registration in PROSPERO: CRD42016033083 and CRD42016033297

Introduction

Over the last two decades, the prevalence of migraine in children has been estimated to reach 10%, increasing with age up to puberty (1,2). According to the International Headache Society (IHS), migraine is a common disabling primary headache disorder (3). In young children, diagnosis of migraine may be difficult as the migraine is defined by subjective symptoms, is highly variable, and it is often susceptible to rapid improvement (4).

It has been indicated recently that there are few reliable trials about pharmacological interventions to relieve the pain of migraine in children, and that using paracetamol or NSAIDs as first-line agents is “widely accepted good clinical practice during acute attacks unless contraindicated” (5).

The World Health Organization Model List of Essential Medicines (WHO EML) contains medicines that are defined by the WHO as those that satisfy priority health care needs of the population (6). The WHO indicates that medicines for inclusion into the WHO EML are identified through an evidence-based process in which quality, safety, efficacy, and cost-effectiveness are the key selection criteria (7). The idea behind the WHO EML is that the use of a limited number of well-known and cost-effective medications may improve long-term medicine supply, lower the costs, and enable better health care provision (8).

The master WHO EML contains a limited number of analgesics for treatment of acute attacks of migraine: Acetylsalicylic acid, ibuprofen, and paracetamol (also known as acetaminophen) (7). The master list has a sub-list, which specifies medicines for children. Only ibuprofen and paracetamol are included as analgesics for acute migraine attacks in the children list. They are important therapeutic options in acute attacks, based on accepted good clinical practice and indirect evidence derived from studies in adults (9,10). Nevertheless, it is important to assess whether direct evidence is available, as this would increase the confidence in these medicines.

The aim of this study was to systematically analyze randomized controlled trials (RCTs) and systematic reviews (SRs) about analgesics listed on the WHO EML for the treatment of acute migraine attack in children, assessing the extent of experimental evidence that supports their inclusion in the WHO EML for this indication. We also evaluated how this evidence was synthesized in SRs, and if there are discordances on the therapeutic value of these medicines.

Methods

Study design

We conducted a SR of the literature, followed by an overview of SRs. We reported the study according to the PRISMA guidelines (11).

Antimigraine analgesics on the WHO EML for children

Firstly, we determined which analgesics are listed as antimigraine medications on the WHO EML for children and accompanying corrigenda. All drugs classified in the N02A, N02B, M01A and M02A groups of the Anatomical Therapeutic Chemical (ATC) classification system of active substances (13) were searched for their presence in the WHO EML for children under indication 7. Antimigraine medicines. The only analgesics found with this indication were ibuprofen and paracetamol, and they were found under the subheading “7.1 For treatment of acute attack” (5). Subsequently, a priori protocols for conducting SRs of literature on these two drugs were designed and registered in the PROSPERO database (registration numbers: CRD42016033083 and CRD42016033297).

Information sources and literature search

Five databases were searched, including Embase and MEDLINE via OVID, Cochrane Database of Systematic Reviews (CDSR), Database of Reviews of Effects (DARE) and Cochrane Central Register of Controlled Trials (CENTRAL) via the Cochrane Library. A search strategy for MEDLINE was designed first, using keywords for headache disorders, children, ibuprofen and acetaminophen (Table 1) and searches for the other databases were adapted accordingly. The last database search was conducted on 18 April 2017. There were no search limits. Studies published in any language were considered for inclusion. Search results from all five databases were exported in a library of the reference management software EndNote X5 (Thomson Reuters, New York, NY, USA), and duplicates were removed.

Table 1.

Search strategy for MEDLINE.

1. exp Headache Disorders/

2. Headache/

3. (migrain* or headache* or cephalgi* or cephalalgi*).mp.

4. 1 or 2 or 3

5. exp child/

6. exp Infant/

7. exp adolescent/

8. exp Pediatrics/

9. (child* or adolescen* or kid or kids or youth* or youngster* or minor or minors or teen* or juvenile* or student* or pupil or pupils or boy or boys or girl or girls or under 18* or underage 18* or under eighteen* or under age* or pediatric* or paediatric*).ti,ab,kw.

10. 5 or 6 or 7 or 8 or 9

11. Acetaminophen/

12. (acetaminophen or paracetamol or Panadol or Tylenol).mp.

13. Ibuprofen/

14. (ibuprofen or Brufen or Advil or Motrin or Nurofen).mp.

15. 11 or 12 or 13 or 14

16. 4 and 10 and 15

Screening and data extraction

Bibliographic records retrieved by database search, consisting of titles and abstracts, were screened by two authors each (AJK, MJ, NS) independently to assess their eligibility. Disagreements were resolved by discussion and involvement of the third author (LP). Full texts of all potentially-includible studies were retrieved and analyzed by two authors independently (MJ, NS), whereas disagreements were resolved by discussion and involvement of the third author (LP). References and citations of included studies were downloaded from Web of Science and screened by two authors independently (MJ, LP) to identify additional citations that may have been missed through electronic database searching methods.

Inclusion criteria

We included randomized controlled trials (RCTs) and SRs analyzing ibuprofen and/or paracetamol as a pharmacological intervention for the treatment of acute attacks of migraine in children < 18 years. A SR was defined as a review with a clearly formulated question that used systematic and explicit methods to identify, select and critically appraise relevant research and to collect and analyze data from the studies that were included in the review (14). As such, the review had to describe a detailed search of the literature for relevant studies and provide a synthesis of the results. For reviews with updates (e.g. Cochrane reviews), only the latest version was included.

Exclusion criteria

Reviews by a single author were excluded even if they had certain other elements of a systematic review methodology (i.e. searching specific databases) because abstract screening, data extraction and quality assessment need to be performed in duplicate to reduce potential errors.

Data items and data extraction process

Data were extracted into the a priori developed data extraction form, which was piloted among the team members. Data items from included studies were extracted by two authors independently (NS, LP). Discrepancies in data extraction were noted and resolved via discussion or, if necessary, by the third author (MJ).

The following data were extracted: First author, year of publication, type of study, language of publication, number of participants, population included in the study, type of study, study setting and country. Additionally, the following outcome data were extracted from RCTs: Pain-free at 2 h, pain relief at 2 h, adverse events, and the following data from SRs: Studied topic, outcomes, and conclusions from abstracts, or from the text if there was no conclusion in the abstract.

Risk of bias assessment in included trials

We assessed RCT quality using the Cochrane risk of bias tool, which includes seven dimensions: Sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessors, incomplete outcome data, selective outcome reporting, and other potential threats to study validity. Quality of SRs was analyzed using a measurement tool to assess the methodological quality of systematic reviews (AMSTAR) (15).

Data synthesis

Meta-analysis for the three comparisons (ibuprofen versus placebo, paracetamol versus placebo, and paracetamol versus ibuprofen) was conducted using RevMan software version 5.3 (Cochrane Review Manager Version 5.3; Nordic Cochrane Centre, Cochrane Collaboration, Copenhagen, Denmark). Random-effects meta-analysis was conducted and results shown as odds ratio (OR) and 95% confidence interval (95% CI). Heterogeneity was analyzed and reported. For meta-analyses, trials adopting a cross-over design were combined with those using parallel groups. The data in the cross-over trials were presented per treatment group, as if the trials had parallel group design. This approach ignores cross-over design, giving the same point estimate as if cross-over was taken into account, but resulting in larger confidence intervals (16). This also has influence on the overall meta-analysis estimates, again producing slightly more conservative estimates.

Conclusiveness of evidence

Conclusiveness of evidence from SRs was analyzed by two authors independently (AJK, LP), whereas evidence for each medicine was rated as either positive, negative, or inconclusive. Evidence was rated as positive if the conclusion was in favor of an intervention, negative if an intervention was inferior compared to the comparator, and inconclusive if the authors indicated that there was not enough evidence to enable conclusions.

Quality of evidence assessment for analyzed outcomes

Strength of evidence for the key outcomes was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology (17). The GRADE system uses the following assessment criteria for levels of evidence: High, moderate, low, or very low. High level indicates that we are very confident that the true effect lies close to that of the estimate of the effect. Moderate level is defined as being moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. With low quality level, our confidence in the effect level is limited; the true effect may be substantially different from the estimate of effect. Very low quality level indicates that we have very little confidence in the effect estimate; the true effect is likely to be substantially different from the estimate of effect (18). The grade for an outcome was decreased if we found serious (−1) or very serious (−2) limitations to study design; important inconsistency(ies) (−1); some (−1) or major (−2) uncertainty about directness; imprecise or sparse data (−1) and high probability of reporting bias (−1).

GRADE assessment was conducted for the following outcomes: pain-free at 2 h, pain relief at 2 h and adverse events. We selected these outcomes because they are primary outcomes frequently used in migraine trials (19). The assessment is presented in the Summary of findings (SoF) tables for relevant comparisons, including paracetamol versus placebo, ibuprofen versus placebo and paracetamol versus ibuprofen. The SoF tables include key information about the quality of evidence, the magnitude of effect of the interventions examined, as well as the sum of available data on the main outcomes. SoFs were created using the online GRADE software (GRADEpro 2015, GRADE Working Group, McMaster University, Hamilton, ON, Canada).

Results

The database search yielded 2692 bibliographic records. After excluding duplicates, screening and excluding irrelevant studies, 84 studies were analysed in full text; 71 studies were excluded and 13 were included (Figure 1). The list and characteristics of excluded studies are available on request. Among included studies there were three RCTs and 10 SRs. Characteristics of RCTs and their risk of bias are summarized in Tables 2 and 3, respectively; SRs are summarized in Table 4.

Figure 1.

Study flow diagram.

Table 2.

Characteristics of included randomized controlled trials.

Study	No of children	Age of children	Intervention and comparison	Outcomes
Hamalainen, 1997 (20)	Randomized: 106 Completed: 88	4–16 years	Three attacks per child were treated in random order with single oral doses of 15 mg/kg paracetamol, 10 mg/kg ibuprofen, and placebo at home	After 2 h: Pain free, complete headache relief, pain relief from grades 4/5 or 5/5 by 2 grades, pain relief from grades 3/5, 4/5, or 5/5 by 1 grade, Relief from grade 2/5 to grade 1/5, Fell asleep ≤ 2 hours, no change, worse, rescue medication ≤ 2 h, rescue medication ≥ 2 h
Lewis, 2002 (21)	Randomized: 138 Completed: 84	6–12 years	One attack per child treated in random order with single doses of ibuprofen suspension 7.5 mg/kg, and placebo suspension	Cumulative proportion of responders (headache severity defined as moderate, severe, none or mild) at 30, 60, 90, 120, 180 and 240 minutes; the time to response, cumulative proportions of subjects with no nausea, vomiting, photophobia, or phonophobia at 30, 60, 90, 120, 180, and 240 minutes; the proportion of subjects experiencing recurrence of migraine headache from 4 to 24 hours; and the proportion of subjects using rescue medication during the 4-hour evaluation period
Evers, 2006 (22)	Randomized: 32 Completed: 29	6–18 years	Cross-over trial. The children received the study drugs for the next three migraine attacks to treat them at home. Study drugs were oral zolmitriptan 2.5 mg, ibuprofen 200 mg (for children under 12) or ibuprofen 400 mg (for adolescents), and placebo	Headache pain intensity (none, mild, moderate, severe) Pain relief at 0.5–24 h, pain free at 0.5–24 h, frequency of accompanying symptoms and adverse events at baseline and at 0.5–24 hours, headache recurrence, sustained pain-free response, rescue medication

Table 3.

Risk of bias in the included RCTs.

Study	Random sequence generation	Allocation concealment (selection bias)	Blinding of participants and personnel (performance bias)	Blinding of outcome assessment (detection bias)	Incomplete outcome data (attrition bias)	Selective reporting (reporting bias)	Other bias
Hamalainen, 1997 (20)	Unclear. Random sequence generation method not described	Unclear. Allocation concealment method not described	Low. Double-blind study	Unclear. Blinding of outcome assessment was not described	Unclear. Overall attrition was 17%, but attrition per group was not described	Low. There is no study protocol published, but all outcomes mentioned in the methods were reported in results	High. Sample size < 50 participants in each arm
Lewis, 2002 (21)	Unclear. Random sequence generation method not described	Unclear. Allocation concealment method not described	Low. Double-blind study	Unclear. Blinding of outcome assessment was not described	High. Overall attrition was 39%. Attrition per group was not described	Unclear. There is no study protocol published. Safety outcomes were listed in the methods, but not reported in results	High. Sample size < 50 participants in each arm
Evers, 2006 (22)	Unclear. Random sequence generation method not described	Unclear. Allocation concealment method not described	Low. Double-blind study	Unclear. Blinding of outcome assessment was not described	Unclear. Overall attrition was 9%, but attrition per group was not described	Low. There is no study protocol published, but all outcomes mentioned in the methods were reported in results	High. Sample size < 50 participants in each arm

Table 4.

Characteristics of included systematic reviews.

Systematic review	Included studies	Databases searched (period of search)	Aim of study	Patients	RCTs included about paracetamol and ibuprofen	Exclusion criteria	Outcomes	Meta-analysis: Yes or no
Bailey, 2008 (24)	RCT	CDSR, DARE, CENTRAL, MEDLINE, Embase; (22 July 2007).	To evaluate which treatments could be effective in the emergency department (ED) for children with migraine and status migrainosus	Children (≤18 years of age) with acute migraine attacks	Paracetamol: 1 (Hamalainen 1997) Ibuprofen: 3 (Hamalainen 1997, Lewis 2002, Evers 2006)	Patients on prophylaxis, non-RCT studies	Pain relief, pain free, recurrence, need for rescue medication	No
Barnes, 2009 (25)	Systematic reviews, RCTs	Medline, Embase, CDSR, CENTRAL, DARE, HTA, NICE (up to 2008.)	We conducted a systematic review and aimed to answer the following clinical question: What are the effects of treatments for acute attacks, and of prophylaxis for migraine headache in children?	Children younger than 18 years of age	Paracetamol: 0 Ibuprofen: 1 (Evers 2006)	Studies that do not explicitly use criteria that are congruent with IHS diagnostic criteria (or revised IHS criteria in children < 16 years of age)	Symptom relief (pain, measured on visual analogue scales; nausea; duration and frequency of headache); functional impairment (measured by behavioural scores, sleep scores, sleep satisfaction scores); migraine recurrence; adverse effects	No
Damen, 2005 (26)	RCT and controlled clinical trials	Medline, Embase, PsychInfo, Web of Science, and Cinahl; (from inception to June 2004).	The objective of this review is to describe and assess the evidence from randomized and clinical controlled trials concerning the efficacy and tolerability of symptomatic treatment of migraine in children	Children younger than 18 years of age	Paracetamol: 1 (Hamalainen, 1997) Ibuprofen: 2 (Hamalainen 1997, Lewis 2002)	Not described	Clinical improvement (headache diaries), effectiveness of drugs, headache index, frequency, intensity or duration, rescue medication, and adverse events post-treatment and at follow-up	No
Lewis, 2004 (27)	–	Medline and Current Contents; (1980 through December 2003)	To review evidence on the pharmacologic treatment of the child with migraine headache	Children from 3 years to 18 years of age	Paracetamol: 1 (Hamalainen, 1997) Ibuprofen: 2 (Hamalainen 1997, Lewis 2002)	Articles reporting studies with ≤ 10 patients	Pain relief, need for rescue medications and adverse events	No
Manzano, 2010 (28)	RCT	Medline, Embase (March 9, 2009)	To review evidence supporting the concept that ibuprofen is superior to acetaminophen for the treatment of benign headaches	Children 4–18 years of age	Paracetamol: 1 (Hamalainen, 1997) Ibuprofen: 1 (Hamalainen 1997)	IHS diagnostic criteria	Pain reduction (5-faces scale or VAS) and duration of effect	No
O'Brien 2012 (29)	RCT, meta-analyses and reviews	PubMed (December 2011)	This review examines the studies that have been performed in pediatric patients, in addition to exploring the treatment options commonly used in pediatrics and adolescents for migraine and their rationale for use	Pediatric patients	Paracetamol: 1 (Hamalainen, 1997) Ibuprofen: 3 (Hamalainen 1997, Lewis 2002, Salucci 2000 – conference abstract)	Not described	Not described	No
Patniyot 2016 (32)	RCTs, retrospective reviews, review articles, and case studies	Scopus, Medline, PubMed (8 December 2014)	We sought to conduct a qualitative systematic review to evaluate the safety and efficacy of available treatments for pediatric patients with migraine or benign primary headache in the ED, in an effort to inform future practice and research	Pediatric patients (age less than 18 years)	Paracetamol: 1 (Hamalainen, 1997) Ibuprofen: 2 (Hamalainen 1997, Lewis 2002)	Studies in a language other than English, dealt with secondary headache disorders (concussion, TBI, mild head injury, stroke), and if they pertained to headache diagnosis rather than treatment, such as imaging studies	Not described	No
Richer 2016 (19)	RCT	Cochrane Central Register of Controlled Trials (CENTRAL) (1991 to 2013, Issue 3), OvidSP MEDLINE (1946 to February 2016), Ovid MEDLINE In-Process and Other Non-Indexed Citations (2012 to February 2016), EMBASE (1980 to February 2016), Database of Abstracts and Reviews of Effects (1991 to April 2013), International Pharmaceutical Abstracts (1970 to April 2013), PsycINFO (1806 to April 2013), EBSCOhost CINAHL (Cumulative Index of Nursing and Allied Health) (1937 to April 2013)	To assess the effects of pharmacological interventions by any route of administration versus placebo for migraine in children and adolescents 17 years of age or less. For the purposes of this review, children were defined as under 12 years of age and adolescents 12 to 17 years of age	Children and adolescents up to 17 years	Paracetamol: 1 (Hamalainen 1997) Ibuprofen: 3 (Hamalainen 1997, Lewis 2002, Evers 2006)	Studies involving both pediatric and adult patients unless they reported results separately for the pediatric patients	Primary: percentage of pain-free participants at 2 h, percentage of participants with any adverse event(s). Secondary: Headache relief at 2 h, rescue medication (use of any medication between 2 and 24 hours), headache recurrence (any headache from 2 to 48 hours), presence of nausea at 2 h, presence of vomiting within 2 h	Yes
Silver, 2007 (30)	RCT	Cochrane Controlled Trials Register (CCTR), Medline (search dates not described)	To undertake a meta-analysis of all randomised controlled trials (RCTs) on the acute pharmacologic treatment of children and adolescents with migraine headache	Children and adolescents	Paracetamol: 1 (Hamalainen, 1997) Ibuprofen: 2 (Hamalainen 1997, Lewis 2002)	Not described	Proportion of patients with headache relief and complete pain relief, 2 h post-treatment	Yes
Verhagen, 2006 (31)	RCT and controlled studies	PubMed, Embase, the Cochrane Controlled Trials Register, PsycINFO, CINAHL and Web of Science (June 2004)	To summarize evidence on the effectiveness of current forms of treatment of migraine in children	Children (under 18 years) with migraine	Paracetamol: 1 (Hamalainen, 1997) Ibuprofen: 2 (Hamalainen 1997, Lewis 2002)	Not described	Frequency, intensity and duration of the headache (headache diary), index of recovery and adverse events	“We gave the results for each examination in relative risks (RR) for dichotomous data or standardized mean differences (SMD) for continuous outcomes. Only in case of clinical homogeneity in patient population, intervention and outcome measures, we have summarized the results statistically (pooled). In clinical heterogeneity, we summarized the results based on level of evidence.”

Table 5.

Conclusiveness of evidence about paracetamol and ibuprofen in included systematic reviews (conclusions from the text if not found in the abstract).

SR	Conclusion about paracetamol and ibuprofen	Conclusiveness of evidence on paracetamol	Conclusiveness of evidence on ibuprofen
Bailey, 2008 (24)	Abstract: Ibuprofen and paracetamol were better than placebo for pain relief	Positive	Positive
Barnes, 2009 (25)	No specific conclusions in the abstract. In the text: We found no RCTs of sufficient quality. Despite the absence of strong evidence from RCTs, it is widely accepted good clinical practice that children who have migraine should be offered paracetamol unless contraindicated Despite the absence of strong evidence from large RCTs, it is widely accepted good clinical practice that children who have migraine should be offered NSAIDs such as ibuprofen unless contraindicated	Inconclusive	Positive
Damen, 2005 (26)	Abstract: There is moderate evidence that both acetaminophen and ibuprofen are more effective in reduction of symptoms, 1 and 2 hours after intake than placebo with minor adverse effects. Most treatments have only been evaluated in 1 or 2 studies, which limits the generalizability of the findings	Positive	Positive
Lewis, 2004 (27)	Abstract: Acetaminophen is probably effective and is well tolerated versus placebo. Ibuprofen is effective and well tolerated versus placebo	Positive	Positive
Manzano, 2010 (28)	There is no abstract. Conclusion from the text: Even though ibruprofen is often considered more effective than acetaminophen for the treatment of benign headache, there is minimal evidence in literature to support this belief.	Inconclusive	Inconclusive
O'Brien, 2012 (29)	Abstract: For the acute treatment of migraine, we recommend the use of ibuprofen or acetaminophen for mild, moderate or severe headache	Positive	Positive
Patniyot, 2016 (32)	Abstract: Treatments considered effective for acute migraine or benign primary headache in the analgesic category include ibuprofen, and to a lesser degree acetaminophen	Positive	Positive
Richer, 2016 (19)	Abstract: Paracetamol was not superior to placebo in one small study of 80 children. Low quality evidence from two small trials shows that ibuprofen appears to improve pain freedom for the acute treatment of children with migraine. We have only limited information on adverse events associated with ibuprofen in the trials included in this review	Negative	Positive
Silver, 2007 (30)	Abstract: No conclusion about paracetamol Composite data demonstrate that only ibuprofen and sumatriptan are significantly more effective than placebo in the generation of headache relief in children and adolescents	No conclusion	Positive
Verhagen, 2006 (31)	Abstract Paracetamol and ibuprofen both prove equally effective in the reduction of headache and give fewer side effects than sumatriptan nasal spray. Given the small number of studies and methodological shortcomings in many studies, results should be taken with caution	Positive	Positive

Randomized controlled trials

The three RCTs on ibuprofen and paracetamol were small – a total of 201 children completed the three studies. The age range of the children was somewhat different between the studies: 4−16 years in one study (20), 6−12 in the second (21) and 6−18 in the third (22). The only studied dose of paracetamol was 15 mg/kg. Additionally, the three studies used different doses of ibuprofen, whereas the first two indicated doses per kilogram – 10 mg/kg (20) or 7.5 mg/kg (21), and the third indicated that children under 12 years received 200 mg while older children received 400 mg (22) (Table 2).

Assessment of RCT quality using the Cochrane risk of bias tool indicated that all three trials had unclear or high risk of bias on most of the analyzed domains (Table 3). Two RCTs had high attrition, with 17% attrition in one (20) and 39% in the other (21), without description of attrition per group. This might have consequences, unbalancing the groups for important prognostic factors.

Meta-analyses of randomized controlled trials

Analyses were conducted for three outcomes: Pain-free at 2 h, pain relief at 2 h and adverse events. Different definitions of pain relief were used in each RCT. In Hamalainen et al., pain relief was defined as “Reduction in severe or moderate headache (grades ≥ 3 on a scale of 1 to 6) by two grades” (20). In Lewis et al., pain relief was “those subjects whose headache severity decreases from moderate or severe at baseline to none or mild” (21). In Evers et al., pain relief was defined as “no or mild headache after moderate or severe headache” (22).

Ibuprofen versus placebo in children and adolescents

Outcome 1.1: Ibuprofen was superior to placebo for pain-free at 2 h in the pooled analysis of three studies (Figure 2(a)). The OR was 3.96 (95% CI 1.78 to 8.82; p < 0.0008). Heterogeneity was not significant, although the magnitude of the effects of ibuprofen was moderately different across RCTs (Chi² = 3.23, df = 2, p = 0.20; I² = 38%).

Figure 2.

Comparisons of ibuprofen versus placebo for migraine in children for outcomes pain-free at 2 h, pain relief at 2 h and adverse events.

Outcome 1.2. Ibuprofen was superior to placebo for pain relief at 2 h in the pooled analysis of three studies (Figure 2(b)). The OR was 3.58 (95% CI 2.04 to 6.29; p < 0.001). There was no heterogeneity (Chi² = 1.12, df = 2, p = 0.57; I² = 0%).

Outcome 1.3. There was no difference between ibuprofen and placebo in the number of patients with adverse events in the pooled analysis of two studies (Figure 2(c)). The OR was 1.31 (95% CI 0.50–3.41; p = 0.58). There was no significant heterogeneity (Chi² = 1.37, df = 1, p = 0.24; I² = 27%). One study did not report adverse events, even though in the Methods the authors indicated that the number and characteristics of adverse experiences were recorded (23). It is unlikely that no adverse events were experienced in a study. In fact, the other two studies had several children signaling adverse events. For this reason, we decided not to include the study reporting zero adverse events in the meta-analysis.

Paracetamol versus placebo in children and adolescents

Only one study provided data for the comparison (20). When paracetamol and placebo were compared, there was no statistically significant difference in any of the three outcomes: The number of children that were pain-free at 2 h (OR 1.65, 95% CI 0.66–4.13), the number of children with pain relief at 2 h (OR 1.95, 95% CI 0.82–4.67) and the number of adverse events (OR 0.41, 95% CI 0.12–1.37) (Figure 3). The limited number of patients is likely to reduce the power of this comparison.

Figure 3.

Comparisons of paracetamol versus placebo for migraine in children for outcomes pain-free at 2 h, pain relief at 2 h and adverse events.

Ibuprofen versus paracetamol in children

Likewise, when direct comparison between ibuprofen and paracetamol was made, there was no difference in any of the three outcomes: The number of children that were pain-free at 2 h (OR 2.34, 95% CI 0.96–5.71), the number of children with pain relief at 2 h (OR 1.79, 95% CI 0.73–4.42) and the number of adverse events (OR 2.16, 95% CI 0.63–7.49) (Figure 4). Again, only one study provided data (20).

Figure 4.

Comparisons of ibuprofen versus paracetamol for migraine in children for outcomes pain-free at 2 h, pain relief at 2 h and adverse events.

Included systematic reviews

The 10 included SRs (19,24 –32) were published between 2004 and 2016. None of them exclusively addressed ibuprofen and paracetamol for migraine in children; their scope was broader (Table 4).

The majority were narrative reviews, while only two SRs meta-analyzed the results of the primary studies (19,30). Regarding evidence on paracetamol, nine reviews included Hamalainen et al.; one excluded it, providing reasons. Regarding evidence on ibuprofen, only two SRs (19,24) included all three RCTs.

Conclusions about the efficacy of ibuprofen and paracetamol were discordant. For ibuprofen, nine SRs had positive conclusions and one SR concluded that there was insufficient evidence to draw a conclusion (Table 5). Regarding paracetamol, six SRs reported positive conclusive evidence, two reported positive inconclusive evidence, and one reported negative conclusive evidence (favoring placebo over paracetamol). One SR did not have any conclusion at all regarding paracetamol (Table 5).

Risk of bias in included reviews

Quality of SRs (see Table 6), analyzed using the AMSTAR tool, revealed that the majority of the SRs were of low quality, with six SRs scoring a total between 1 and 3 points, three SRs were of medium quality, scoring between 4 and 6 points, and one SR was of high quality with 11 points. The high-quality SR was a Cochrane systematic review published in 2016.

Table 6.

Methodological quality of included systematic reviews judged with the AMSTAR tool.

	Study
AMSTAR criterion	Bailey 2008	Barnes 2009	Damen 2005	Lewis 2004	Manzano 2010	O'Brien 2012	Patniyot 2016	Richer 2016	Silver 2007	Verhagen 2006
1. Was a priori design provided?	0	1	0	0	0	0	0	1	0	0
2. Was there duplicate study selection and data extraction?	0	0	1	1	1	0	0	1	1	1
3. Was a comprehensive literature search performed?	1	1	1	1	1	1	1	1	1	1
4. Was the status of publication (i.e. grey literature) used as an inclusion criterion?	0	0	0	0	0	0	0	1	0	0
5. Was a list of studies (included and excluded) provided?	0	0	1	0	0	0	0	1	0	0
6. Were the characteristics of the included studies provided?	1	0	1	1	0	0	1	1	1	0
7. Was the scientific quality of the included studies assessed and documented?	1	1	1	0	0	0	0	1	0	1
8. Was the scientific quality of the included studies used appropriately in formulating conclusions?	1	1	1	0	0	0	0	1	0	0
9. Were the methods used to combine the findings of studies appropriate?	0	0	0	0	0	0	0	1	0	0
10. Was the likelihood of publication bias assessed?	0	0	0	0	0	0	0	1	0	0
11. Was the conflict of interest included?	0	0	0	0	0	0	0	1	0	0
Total AMSTAR score	4	4	6	3	2	1	2	11	3	3

AMSTAR scoring: each item is scored 1 if the specific criterion is met, or 0 if the criterion is not met, is unclear or is not applicable. An overall score refers to the sum of individual item scores. Quality ratings are as follows: 8–11 is high quality, 4–7 is medium quality and 0–3 is low quality.

Quality of evidence

The quality level of outcomes, analyzed using the GRADE approach, was presented as SoF tables for the comparisons of ibuprofen versus placebo (Table 7), paracetamol versus placebo (Table 8) and ibuprofen versus paracetamol (Table 9). In the comparison of ibuprofen versus placebo all outcomes were rated as low quality due to high risk of bias. There was a large magnitude of effect, but also wide confidence interval, indicating some imprecision around a potentially large effect. We considered that large effects and imprecision did not warrant up or downgrading of the evidence. In the comparisons of paracetamol versus placebo and ibuprofen versus paracetamol, all outcomes were rated as very low quality due to study limitations (i.e. high risk of bias), indirectness of evidence (wide range of children's ages in trials of paracetamol; different doses of ibuprofen) and imprecision (wide confidence interval and small sample size).

Table 7.

Summary of findings table for Comparison 1: Ibuprofen versus placebo.

Ibuprofen compared to placebo for migraine in children
Patient or population: Migraine in children
Setting: outpatient
Intervention: Ibuprofen
Comparison: Placebo
Outcomes	Anticipated absolute effects* (95% CI)		Relative effect (95% CI)	№ of participants (studies)	Quality of the evidence (GRADE)	Comments
Risk with placebo	Risk with Ibuprofen
Pain-free at 2 h	216 per 1,000	522 per 1,000 (329 to 709)	OR 3.96 (1.78 to 8.82)	225 (3 RCTs)	⊕⊕◯◯ LOW ^a,b
Pain relief at 2 h	405 per 1,000	709 per 1,000 (582 to 811)	OR 3.58 (2.04–6.29)	225 (3 RCTs)	⊕⊕◯◯ LOW ^a,b
Adverse events	118 per 1,000	149 per 1,000 (63 to 314)	OR 1.31 (0.50–3.41)	220 (3 RCTs)	⊕⊕◯◯ LOW ^a,b
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; OR: Odds ratio; RCT: randomized controlled trial.
GRADE Working Group grades of evidence High quality: We are very confident that the true effect lies close to that of the estimate of the effect Moderate quality: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low quality: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect Very low quality: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

Explanations.

For all outcomes, we judged the impact of missing data to be relevant: We decreased the overall quality for limitations (−2).

For all outcomes, we judged the impact of different ages of children and doses of medicines to be unclear: We did not decrease the overall quality for inconsistency.

Table 8.

Summary of findings table for Comparison 2: Paracetamol versus placebo.

Paracetamol compared to placebo for migraine in children
Patient or population: Migraine in children
Setting: Outpatient
Intervention: Paracetamol
Comparison: Placebo
Outcomes	Anticipated absolute effects^* (95% CI)		Relative effect (95% CI)	№ of participants (studies)	Quality of the evidence (GRADE)	Comments
Risk with placebo	Risk with Paracetamol
Pain-free at 2 h	279 per 1,000	390 per 1,000 (203-615)	OR 1.65 (0.66–4.13)	84 (1 RCT)	⊕◯◯◯ VERY LOW ^a,b
Pain relief at 2 h	372 per 1,000	536 per 1,000 (327-735)	OR 1.95 (0.82–4.67)	84 (1 RCT)	⊕◯◯◯ VERY LOW ^a,b
Adverse events	111 per 1,000	49 per 1,000 (15-146)	OR 0.41 (0.12–1.37)	164 (1 RCT)	⊕◯◯◯ VERY LOW ^a,b
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; OR: Odds ratio, RCT: Randomized controlled trial
GRADE Working Group grades of evidence High quality: We are very confident that the true effect lies close to that of the estimate of the effect Moderate quality: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low quality: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect Very low quality: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

Explanations

For all outcomes, we judged the impact of missing data to be relevant: we decreased the overall quality for limitations (−2)

Wide 95% confidence interval considering relative risk and/or absolute events and small sample size. We did decrease the overall quality for imprecision (−1)

Table 9.

Summary of findings table for Comparison 3: Ibuprofen versus paracetamol.

Ibuprofen compared to paracetamol for migraine in children
Patient or population: Migraine in children
Setting: Outpatient
Intervention: Ibuprofen
Comparison: Paracetamol
Outcomes	Anticipated absolute effects^* (95% CI)		Relative effect (95% CI)	№ of participants (studies)	Quality of the evidence (GRADE)	Comments
Risk with paracetamol	Risk with Ibuprofen
Pain-free at 2 h	390 per 1,000	600 per 1,000 (381-785)	OR 2.34 (0.96–5.71)	81 (1 RCT)	⊕◯◯◯ VERY LOW ^a,b
Pain relief at 2 h	537 per 1,000	675 per 1,000 (458-837)	OR 1.79 (0.73–4.42)	81 (1 RCT)	⊕◯◯◯ VERY LOW ^a,b
Adverse events	48 per 1,000	99 per 1,000 (31-275)	OR 2.16 (0.63–7.49)	164 (1 RCT)	⊕◯◯◯ VERY LOW ^a,b
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; OR: Odds ratio, RCT: Randomized controlled trial
GRADE Working Group grades of evidence High quality: We are very confident that the true effect lies close to that of the estimate of the effect Moderate quality: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low quality: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect Very low quality: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

Explanations

For all outcomes, we judged the impact of missing data to be relevant: we decreased the overall quality for limitations (−2)

Wide 95% confidence interval considering relative risk and/or absolute events and small sample size. We decreased the overall quality for imprecision (−1)

Discussion

The WHO EML recommends two analgesics for the treatment of acute migraine attacks in children – ibuprofen and paracetamol. Only three small RCTs about the efficacy and safety of ibuprofen and paracetamol were found. The summarized point estimates indicate a potential large beneficial effect of ibuprofen to reduce pain in children. The results were less compelling for paracetamol, as the reduction of pain was not significant in the analyses. However, the power of this comparison is limited by the inclusion of a single small study. Using GRADE methodology, we are led to conclude that the quality of the evidence is low for ibuprofen and very low for paracetamol.

All included RCTs had high risk of bias, as well as a number of potential problems in the design, conduct and interpretation of their results. In the study by Hamalainen at al., multiple deviations from the original protocol were described (20). In the study by Lewis et al., some patients were allowed to take other prophylactic drugs, introducing a strong confounder in an experimental design (21). Furthermore, the same study concluded that ibuprofen is effective for children and adolescents, particularly boys, whereas efficacy for girls was not established at all. Though there is substantial interest in sex differences in medicine effects, and stratification by sex is common in clinical trials, there is not a strong biological or pharmacological rationale to justify differences in the effectiveness of these analgesics between boys and girls. If subgroup differences are such that only boys or girls deserve treatment with some medicine, this would have major implications for clinical practice, and conclusions should be based on solid ground. Furthermore, the different dose schemes studied in those trials might not be considered equivalent. For example, a 10-year-old boy who weighs 35 kg would be treated with three different doses of ibuprofen: 350 mg, 262.5 mg or 200 mg.

Ten SRs that covered pharmacological treatments of migraine in children varied in terms of their methods and included studies. Conclusions about ibuprofen and paracetamol were discordant. Although the overall conclusion is that ibuprofen and paracetamol are effective for acute migraine attacks in children, very few reviews included all primary studies, meta-analyzed the results of primary studies, or considered the results of quality assessment when drawing conclusions. Evidence about safety was scarce. The methodological quality of the majority of included SRs, judged by the AMSTAR tool, was low.

A limitation of this study is the inability to separate data from primary studies for prepubertal and pubertal children (children and adolescents) because two trials that included both age ranges did not provide separate data for those populations.

The majority of evidence about efficacy and safety of medicines in children comes from studies in adults (33). Evidence related to children is usually derived from pharmacokinetic queries on single drugs in a limited number of subjects (34). However, safety and efficacy profiles of medicines may be significantly different between children and adults because of differences in developmental physiology, disease pathophysiology, or developmental pharmacokinetics and pharmacodynamics (35,36).

Effects of ibuprofen on the pain associated with acute migraine attacks in children were large and consistent across studies. Despite the studies showing some methodological shortcomings, the strong benefit associated with ibuprofen increases our confidence in the therapeutic value of this medicine. Evidence for paracetamol is less straightforward, as direct evidence is limited to one small, inconclusive trial. Nevertheless, this evidence has to be considered in the larger context of evidence derived from pharmacokinetic studies and RCTs conducted in adults.

Public health relevance

Ibuprofen and paracetamol are the only analgesics for migraine in children listed on World Health Organization's Essential Medicines list.

Evidence for efficacy and safety of these drugs relies only on three small trials with a total of 201 children.

Ten systematic reviews have been published about this topic, but no new trials.

We need new trials on this topic to get high-quality direct evidence about efficacy and safety of ibuprofen and paracetamol for migraine in children.

Footnotes

Acknowledgements

We are grateful to Dr Lorenzo Moja and Dr Nicola Magrini of the World Health Organization for participating in formation of the study idea, study conduct and reporting.

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

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