Article

Pharmacologic Treatment of Pediatric Headaches: A Meta-analysis

JAMA pediatrics 01/2013; 167(3):1-11. DOI: 10.1001/jamapediatrics.2013.508
Source: PubMed

ABSTRACT

Objective To assess the effectiveness of prophylactic headache treatment in children and adolescents.
Data Sources PubMed, EMBASE, Cochrane Database of Clinical Trials, and bibliography of retrieved articles through August 11, 2012.
Study Selection Randomized trials of headache treatment among children and adolescents (<18 years old).
Intervention Any placebo-controlled trial or comparisons between 2 or more active medications.
Main Outcome Measure Number of headaches per month.
Results Among 21 included trials, there were 13 placebo-controlled and 10 active comparator trials (2 also included placebo). Twenty trials focused on episodic migraines and 1 on chronic daily headaches. Drugs more effective than placebo for episodic migraines (<15 headaches per month) included topiramate (difference in headaches per month, −0.71; 95% CI, −1.19 to −0.24) and trazodone (−0.60; 95% CI, −1.09 to −0.11). Ineffective drugs included clonidine, flunarizine, pizotifen, propranolol, and valproate. A single trial of fluoxetine for chronic daily headaches found it ineffective. Patients given placebo experienced a significant (P = .03) decline in headaches, from 5.6 (95% CI, 4.52-6.77; Q = 8.14 [Cochran Q is a measure of the heterogeneity of the included studies]) to 2.9 headaches per month (95% CI, 1.66-4.08; Q = 4.72). Among the 10 active comparator trials, flunarizine was more effective than piracetam (difference in headaches per month, −2.20; 95% CI, −3.93 to −0.47) but no better than aspirin, dihydroergotamine, or propranolol. Propranolol was compared with valproate as well as behavioral treatment, and 2 studies compared different doses of topiramate; none of these trials showed significant differences.
Conclusions Topiramate and trazodone have limited evidence supporting efficacy for episodic migraines. Placebo was effective in reducing headaches. Other commonly used drugs have no evidence supporting their use in children and adolescents. More research is needed.

Full-text

Available from: Dorothy A Becher, Nov 18, 2015
JOURNAL CLUB
REVIEW ARTICLE
Pharmacologic Treatment of Pediatric Headaches
A Meta-analysis
Khalil El-Chammas, MD; Jill Keyes, MD; Nathan Thompson, MD; Jayanthi Vijayakumar, MBBS;
Dorothy Becher, MPH; Jeffrey L. Jackson, MD, MPH
Objective: To assess the effectiveness of prophylactic
headache treatment in children and adolescents.
Data Sources: PubMed, EMBASE, Cochrane Database
of Clinical Trials, and bibliography of retrieved articles
through August 11, 2012.
Study Selection: Randomized trials of headache treat-
ment among children and adolescents (18 years old).
Intervention: Any placebo-controlled trial or compari-
sons between 2 or more active medications.
Main Outcome Measure: Number of headaches per
month.
Results: Among 21 included trials, there were 13 placebo-
controlled and 10 active comparator trials (2 also in-
cluded placebo). Twenty trials focused on episodic mi-
graines and 1 on chronic daily headaches. Drugs more
effective than placebo for episodic migraines (15 head-
aches per month) included topiramate (difference in head-
aches per month, 0.71; 95% CI, 1.19 to 0.24) and
trazodone (0.60; 95% CI, 1.09 to 0.11). Ineffective
drugs included clonidine, flunarizine, pizotifen, proprano-
lol, and valproate. A single trial of fluoxetine for chronic
daily headaches found it ineffective. Patients given pla-
cebo experienced a significant (P=.03) decline in head-
aches, from 5.6 (95% CI, 4.52-6.77; Q=8.14 [Cochran Q
is a measure of the heterogeneity of the included studies])
to 2.9 headaches per month (95% CI, 1.66-4.08; Q=4.72).
Among the 10 active comparator trials, flunarizine was more
effective than piracetam (difference in headaches per month,
2.20; 95% CI, 3.93 to 0.47) but no better than aspi-
rin, dihydroergotamine, or propranolol. Propranolol was
compared with valproate as well as behavioral treatment,
and 2 studies compared different doses of topiramate; none
of these trials showed significant differences.
Conclusions: Topiramate and trazodone have limited
evidence supporting efficacy for episodic migraines. Pla-
cebo was effective in reducing headaches. Other com-
monly used drugs have no evidence supporting their use
in children and adolescents. More research is needed.
JAMA Pediatr. 2013;167(3):250-258.
Published online January 28, 2013.
doi:10.1001/jamapediatrics.2013.508
H
EADACHES ARE COMMON IN
children and adolescents.
Just as in adults, tension
headaches are more com-
mon than migraine head-
aches.
1
Up to 15% of children and adolescents
experience tension headachescompared with
4% for migraines.
2-4
Similar to adults, chil-
dren with tension headaches are less likely
to seek medical attention than those expe-
riencing migraine headaches.
1
Migraines
occurthroughout childhoodandadolescence,
although the prevalence increases with age,
from 3% in the preschool age, up to 11% in
the elementary age, and reaching as high as
23% during high school.
5
Among children,
more boys than girls have migraines, but this
is reversed after puberty.
6
The diagnostic criteria for migraine
headaches have evolved over time.
Whereas early definitions emphasized the
difference between tension and migraine
headaches and migraines with and with-
out aura, modern migraine classification
also includes frequency as a criterion, with
episodic headaches occurring up to 14 times
per month and chronic headaches 15 or
more times. The diagnosis of migraines in
children and adolescents is even more chal-
lenging owing to the wide variety in symp-
toms, including abdominal pain, and be-
See also pages 300
and 308
CME available online at
www.jamanetwork.com/cme.aspx
and questions on page 216
Journal Club slides available
at www.jamapeds.com
Author Aff
Departmen
(Drs El-Ch
Thompson
)
(Drs Vijaya
Medical Co
Milwaukee
Services U
n
Maryland (
Author Affiliations:
Departments of Pediatrics
(Drs El-Chammas, Keyes, and
Thompson) and Medicine
(Drs Vijayakumar and Jackson),
Medical College of Wisconsin,
Milwaukee; and Uniformed
Services University, Bethesda,
Maryland (Ms Becher).
JAMA PEDIATR/ VOL 167 (NO. 3), MAR 2013 WWW.JAMAPEDS.COM
250
©2013 American Medical Association. All rights reserved.
Downloaded From: https://archpedi.jamanetwork.com/ on 01/27/2014
Page 1
cause headache can be experienced as a manifestation of a
symptom complex due to a particular condition or mecha-
nism, such as epilepsy or mitochondrial disorders.
Pharmacologic headache treatment can be either abor-
tive or prophylactic. Abortive treatment is used for acute
headaches, and the aim of prophylactic treatment is to
reduce the frequency or severity of headaches. A variety
of prophylactic treatment options are available.
7
Com-
mon ones include antiepileptics (eg, sodium valproate,
gabapentin, topiramate, levetiracetam, and zonisamide),
8-12
antidepressants (eg, amitriptyline, trazodone, and
pizotifen),
13-16
antihistamines (eg, cyproheptadine),
16,17
calcium channel blockers (eg, flunarizine and
nimodipine),
18,19
antihypertensive agents (eg, proprano-
lol, timolol, and clonidine),
20-22
and nonsteroidal anti-
inflammatory drugs (eg, naproxen).
23
The decision as to
which agent to use typically depends on the patient’s co-
morbid conditions and the effect profile of the medica-
tion. To help with this decision, we conducted a meta-
analysis to determine the comparative effectiveness and
adverse effects of different pharmacologic prophylactic
treatments of headaches in children and adolescents.
METHODS
This report closely adheres to PRISMA (Preferred Reporting Items
for Systematic Review and Meta-Analyses) recommendations for
reporting on systematic reviews.
24
We searched PubMed, EMBASE,
bibliographies of all retrieved articles and published systematic
reviews, and the Cochrane Database of Clinical Trials for each of
the classes of medications (
Table 1) through August 11, 2012,
without language restriction. We included published random-
ized controlled trials that evaluated efficacy in reducing the fre-
quency or severity of headaches in children and adolescents (18
years of age). Included trials could report on migraine, tension,
or chronic daily headache and could include either placebo or
comparisons between 2 or more active medications. Screening
for included trials was a 2-stage procedure. The titles and ab-
stracts of all retrieved articles were reviewed in duplicate by at
least 2 of us. Potential articles were retrieved in full and re-
viewed for eligibility. This process was divided among the au-
thors by drug class, with more than 1 reviewer for each class. Dis-
agreements were resolved by group consensus.
Data were abstracted independently by at least 2 of us. Be-
cause headache measures can vary, a priori we intended to fol-
low International Headache Society (IHS) recommendations
25
by abstracting headache outcome measures in this order: head-
ache frequency, headache index (including frequency), head-
ache severity, headache duration, and patient preference. How-
ever, all included studies reported headache frequency, which
was our primary outcome.
When studies used repeated measures analyses with vari-
ance assessed based on change from baseline values, we trans-
formed this measure into an absolute measure of headaches per
month. The number of headaches per month was pooled using
the DerSimonian and Laird random effects model.
26
We se-
lected the most common time point (12 weeks) as our pri-
Table 1. Search Strategy
Search Purpose Search Strategy
Headaches (headache OR headache disorders OR migrain* OR headache* OR cephalgi* OR cephalalgi* OR tension*)
Randomized controlled trials AND (randomized controlled trial [pt] OR controlled clinical trial [pt] OR randomized controlled trials [mh] OR random
allocation [mh] OR double-blind method [mh] OR single-blind method [mh] OR clinical trial [pt] OR clinical trials
[mh] OR (“clinical trial” [tw]) OR ((singl* [tw] OR doubl* [tw] OR trebl* [tw] OR tripl* [tw]) AND (mask* [tw] OR
blind* [tw])) OR (placebos [mh] OR placebo* [tw] OR random* [tw] OR research design [mh:noexp] OR
comparative study [mh] OR evaluation studies [mh] OR follow-up studies [mh] OR prospective studies [mh] OR
control* [tw] OR prospectiv* [tw] OR volunteer* [tw]) NOT (animals [mh] NOT humans [mh])
Pediatric “Child”[MeSH Terms] OR “adolescent”[MeSH Terms] OR pediatric)
-Blockers (“Adrenergic alpha-Antagonists” [MeSH Terms] or clonidine OR tizanidine)
Angiotension-converting
enzyme inhibitors
“Angiotensin-Converting Enzyme Inhibitors” [mh] OR benzapril OR captopril OR enalapril OR lisinopril OR moexipril
OR perindopril OR quinapril OR ramipril OR trandolapril
Angiotension receptor
blockers
“Angiotensin Receptor Antagonists” [mh] OR losartan OR irbesartan OR olmesartan OR candesartan OR valsartan OR
telmisartan
Anticonvulsants (anticonvulsants [mh] OR anticonvulsant* OR antiepileptic* OR acetazolamide OR carbamazepine OR chlormethiazole
OR clobazam OR clorazepate OR divalproex OR ethosuximide OR felbamate OR fosphenytoin OR gabapentin OR
lamotrigine OR levetiracetam OR mephobarbital OR methsuximide OR midazolam OR oxcarbazepine OR
paraldehyde OR pentobarbital OR phenobarbital OR phenytoin OR primidone OR valproate OR tiagabine OR
topiramate OR valproic* OR vigabatrin OR zonisamide)
-Blockers Adrenergic -receptor blockaders [mh] OR (alprenolol OR bucindolol OR carteolol OR carvedilol OR labetalol OR
nadolol OR penbutolol OR pindolol OR propranolol OR sotalol OR timolol OR acebutolol OR atenolol OR betaxolol
OR bisoprolol OR celiprolol OR esmolol OR metoprolol OR nebivolol)
Calcium channel blockers (calcium channel blockers/therapeutic use”[mh] OR amlodipine OR aranidipine OR azelnidipine OR barnidipine OR
benidipine OR bepridil OR cilnidipine OR clevidipine OR diltiazem OR efonidipine OR felodipine OR fendiline OR
flunarizine OR fluspirilene OR gallopamil OR isradipine OR lacidipine OR lercanidipine OR manidipine OR mibefradil
OR nicardipine OR nifedipine OR nilvadipine OR nimodipine OR nisoldipine OR nitrendipine OR pranidipine OR
verapamil)
Selective serotonin
reuptake inhibitors
Serotonin uptake inhibitors/therapeutic use [mh] OR (citalopram OR dapoxetine OR escitalopram OR fluoxetine OR
fluvoxamine OR indalpine OR paroxetine OR sertraline OR vilazodone OR zimelidine OR venlafaxine OR
desvenlafaxine OR duloxetine OR milnacipran OR levomilnacipran OR sibutramine OR bicifadine)
Serotonin agonist (pizotifen) Pizotyline [mh] OR pizotifen OR sandomigran
Tricyclic antidepressants Antidepressive agents, tricyclic OR antidepressive$ OR tricyclic$ OR amitriptyline OR amoxapine OR clomipramine
OR desipramine OR dibenzepin OR dothiepin OR doxepin OR imipramine OR lofepramine OR nortriptyline OR
opipramol OR protriptyline OR trimipramine
JAMA PEDIATR/ VOL 167 (NO. 3), MAR 2013 WWW.JAMAPEDS.COM
251
©2013 American Medical Association. All rights reserved.
Downloaded From: https://archpedi.jamanetwork.com/ on 01/27/2014
Page 2
mary analysis, although we calculated pooled estimates for each
drug at all time points reported. In addition to pooling data for
individual drugs, we also pooled data from drugs with similar
mechanism of actions (eg, -blockers, dihydropyridines, se-
lective serotonin reuptake inhibitors, and tricyclic antidepres-
sants). We also looked at placebo response by pooling the fre-
quency of headaches at each time point among patients receiving
placebo treatment and comparing these data with those in other
treatment groups using random effects meta-regression.
Some studies also reported a dichotomous outcome, improve-
ment in headaches. For this outcome, we also followed IHS guide-
lines and included this outcome only if subjects experienced at least
50% improvement. We assessed article quality independently and
in duplicate using a component approach based on the Cochrane
Risk of Bias Tool
27
and the Jadad scale,
28
with good interrater agree-
ment (Cochrane intraclass correlation coefficient, 0.83; Jadad ,
0.85). Jadad includes 5 questions of study quality (randomization,
blinding, completeness of follow-up, statistical method, inclusion/
exclusion criteria, and adverse effects). Scores can vary from 0 to
8. Disagreements were resolved by consensus.
For crossover trials, we followed the recommendations of
the Cochrane collaboration by reducing the sample size for cross-
over trials by 50%
29
and pooled both arms of the crossover; all
studies reported no carryover effect. If studies had reported a
carryover effect, we planned to pool only the first half of the
study, effectively reducing the sample size by 50% and con-
verting a crossover trial to a parallel study.
We assessed the presence of heterogeneity visually using Gal-
braith plots
30
and the I
2
statistic.
31
We planned a priori to conduct
heterogeneity assessments on age, sex, study duration, study size,
study design (parallel vs crossover), baseline headache frequency,
and the Jadad and Cochrane quality characteristics (with a scaled
Records identified through database searching2893
α-Adrenergic agonists (n
=
246)
Anticonvulsants (n
=