Current Neurology and Neuroscience Reports (2020) 20:15

https://doi.org/10.1007/s11910-020-01035-5

HEADACHE (R.H. SINGH, SECTION EDITOR)

ED and Inpatient Management of Headache in Children

and Adolescents
Elizabeth Troy 1 & Marcy Yonker 1

# Springer Science+Business Media, LLC, part of Springer Nature 2020

Abstract
Purpose of Review Pediatric migraine is common, and appropriate abortive treatment is important to limit impact on school
performance and mental health. This review will describe the latest evidence for abortive treatment in the emergency department
and inpatient settings.
Recent Findings It is recognized that a protocol for emergency department treatment can increase efficacy and prevent admis-
sions. These protocols commonly include a non-opioid analgesic and dopamine receptor antagonist. A novel approach to
treatment with valproic acid is use of a continuous infusion. Administration of ketamine or propofol and peripheral nerve blocks
could add more expedited treatment options to the armamentarium for pediatric migraine.
Summary There is increasing variety in the abortive treatment of pediatric migraine, but continued research is necessary for
validation of these approaches.

Keywords Pediatric migraine . Adolescent . Abortive . Emergency room . Inpatient

Abbreviations and requires early treatment in effort to decrease the morbidity

ED emergency department associated with poor school performance and increased psy-
AAN American Academy of Neurology chosocial stress. It has been described that patients treat mi-
VPA valproic acid graine at home for ~ 2 days [1, 2] prior to presenting to the
DHE dihydroergotamine emergency department (ED) for additional treatment. At-
NSAID non-steroidal anti-inflammatory drug home treatment typically includes over-the-counter medica-
intravenous IV tions such as ibuprofen and acetaminophen, in addition to
DRA dopamine receptor antagonist prescription medications, such as triptans.
NMDA N-methyl-D-aspartate Pediatric patients who present to the ED with migraine are
PNB peripheral nerve block most likely to be adolescent females. The largest multi-center
study describing 32,124 pediatric patients seen for migraine
across 35 US-based hospitals reported that the median age is
14 years and 67% are female [2], which is supported by more
Introduction recent literature [3, 4]. Up to 17% of patients are admitted
from the ED due to treatment failure [2–6]. A recent article
Pediatric migraine is a common diagnosis seen by pediatri- by the American Academy of Neurology (AAN) entitled
cians, emergency medicine physicians, and child neurologists Practice guideline update summary: Acute treatment of mi-
graine in children and adolescents focuses on the use of acet-
This article is part of the Topical Collection on Headache
aminophen, ibuprofen, and triptans, as well as the appropriate
counseling for how to use these medicines, but does not in-
* Elizabeth Troy
Elizabeth.Troy@childrenscolorado.org clude recommendations for ED and inpatient abortive treat-
ment [7].
1
In recent years, ED protocols for abortive migraine treat-
Department of Pediatrics (Neurology), University of Colorado
School of Medicine and Children’s Hospital of Colorado, 13123 E.
ment have been published, which include various approaches
16th Ave, B155, Aurora, CO 80045, USA to use of IV fluids, non-opioid analgesics, dopamine receptor
 15 Page 2 of 6
antagonists, diphenhydramine, valproic acid (VPA), magne-
sium, and dihydroergotamine (DHE) for the treatment of pe-
diatric migraine [3, 8, 9•], but only a single article has studied
the effect on outcomes before and after protocol implementa-
tion [9•]. Leung et al. describes a cohort of 165 patients prior
to and 87 patients after implementation, and they demonstrat-
ed a decrease in absolute pain score (6.9 vs 5.3, p ≤ 0.001),
decrease in length of stay (4.4 vs 5.3 h; p = 0.008), and de-
crease in admission rates (3% vs 32%, p ≤ 0.001) [9•]. In this
article, we will describe the latest evidence of specific treat-
ments of migraine in the emergency department and inpatient
settings.
Case Presentation
Patient is a 14-year-old female (47 kg) with migraine without
aura who presented to the emergency department for 3 days of
headache, described as an 8 out of 10 pulsating left
frontotemporal headache associated with nausea, photopho-
bia, and phonophobia. She denies vision changes, paresthe-
sias, or weakness. There is not a positional component. Prior
to presenting to the ED, she administered rizatriptan 10 mg
and ibuprofen 400 mg followed by a repeat dose of rizatriptan
10 mg 2 h later. Although this regimen had previously aborted
her migraines, this time it reduced her headache from a 9 to 8
out of 10.
Treatment
Analgesics
Non-opioid analgesics are the most common medication used
in the emergency department for the treatment of migraine.
Bachur et al. report that 66% of patients receive this type of
medication in the ED [2]. In the inpatient setting, non-steroidal
anti-inflammatory agents (NSAID) are 4th most common
medication and are given to 43% of patients [10]. These med-
ications can be used as monotherapy for patients with milder
headaches or in combination with other classes of medications
for more severe headaches [3].
Brousseau et al. explored the efficacy of intravenous (IV)
fluids in conjunction with either ketorolac or prochlorperazine
in a randomized, double-blinded 2-center trial of 62 children.
They demonstrated treatment success, defined as > 50% re-
duction in pain score within 60 min, for 55% of patients re-
ceiving ketorolac with a 31% recurrence within 48 h.
Prochlorperazine demonstrated 85% treatment success and
27% recurrence within 48 h. For patients who failed the initial
treatment, they were allowed to cross over to the other study
arm. 4/4 (100%) that crossed over to ketorolac achieved treat-
ment success, and 8/12 (66%) that crossed over to
Curr Neurol Neurosci Rep (2020) 20:15
prochlorperazine achieved treatment success [11]. Although
this study suggests that prochlorperazine is superior to
ketorolac, these medications are frequently used together in
clinical practice rather than in isolation.
Dopamine Receptor Antagonists
Dopamine receptor antagonists (DRAs) are also a common
class of medication used in the abortive treatment of migraine
as they have both analgesic and anti-nausea properties.
Frequency of use in the pediatric ED and inpatient setting is
39–50% [2, 12] and 67% [10], respectively.
There have been several studies in recent years investigat-
ing the use of DRAs. Bachur et al. is a multi-center retrospec-
tive study of 32,124 children with migraine seen in pediatric
academic EDs from 2009 to 2012 that investigates the vari-
ability in abortive treatment. 50% of patients received a DRA.
Specifically, 48% received metoclopramide, 47% received
prochlorperazine, and 5% received promethazine. These med-
ications were most commonly used in combination rather than
in isolation. The use of metoclopramide was associated with a
31% increased odds of return visit within 3 days when com-
pared with prochlorperazine. This was not seen in
promethazine [2].
Sheridan et al. is a single-center retrospective study inves-
tigating the efficacy of various DRAs in conjunction with an
NSAID in 67 pediatric ED visits for 57 unique patients. The
choice of DRA was at the discretion of the treating physician,
and the rate of use for each was 40% prochlorperazine, 34%
metoclopramide, and 25% promethazine. The use of diphen-
hydramine was also at the discretion of the treating physician
and was used in 89% of prochlorperazine cohort, 74% of
metoclopramide cohort, and 65% of promethazine cohort.
Treatment failure was seen in 9% for prochlorperazine, 25%
for metoclopramide, and 43% for promethazine. In compari-
son with patients receiving prochlorperazine, the use of
promethazine was associated with an 11 times increased odds
of treatment failure (p = 0.01) and decreased absolute pain
reduction by 2.2 (p = 0.018). These outcomes were not statis-
tically significant between prochlorperazine and
metoclopramide [4]. This study did not control for diphenhy-
dramine, so it is unclear if its use contributed to efficacy.
Kabbouche et al. describe a cohort of 20 patients with mi-
graine who presented to the ED and received treatment with
prochlorperazine and IV hydration. At 1-h post-infusion, 90%
(18/20) of patients had an improved pain score with absolute
mean pain reduction of 8.4 to 1.6 (p < 0.0001), and 60% (12/
20) achieved headache freedom. At 3 h post infusion, 95%
(19/20) of patients experienced a ≥ 50% reduction with 65%
(13/20) achieving headache freedom. At 24 h follow-up, 90%
(18/20) had achieved headache freedom [1]. The authors do
not comment on if additional treatments were given post-dis-
charge, so it is unclear if additional medications and/or time
Curr Neurol Neurosci Rep (2020) 20:15
alone contributed to improved headache freedom from 3 h
post-treatment to 24 h post-discharge.
There is a single paper in the literature describing the use of
chlorpromazine in the treatment of pediatric migraine. This
retrospective cohort study compares the use of IV fluids and
ketorolac in conjunction with IV chlorpromazine versus
prochlorperazine. In comparison with prochlorperazine, chlor-
promazine had a higher failure rate (40% vs 15%, p = 0.0001),
need for additional abortive treatment (29% vs 10%,
p < 0.0001), and rate of admission (16% v 5%, p < 0.0008).
The rate of return visit within 48 h was not statistically signif-
icant between the 2 groups [13]. The authors report that time
to initial medication was significantly longer in the chlor-
promazine group than in the prochlorperazine group, and it
is uncertain if this delay contributed to a difference in
outcomes.
Antihistamines
Diphenhydramine has dual purpose in the treatment of mi-
graine as it has anti-nausea properties but is also used to pre-
vent extrapyramidal side effects seen with DRAs. There have
not been any pediatric studies to date to separate indications
for use. In the ED and inpatient settings, diphenhydramine is
administered in 14–33% [2, 12, 14] and 40% [10],
respectively.
There is a paucity of studies in the pediatric population that
investigate diphenhydramine use as monotherapy for the abor-
tive treatment of migraine. Bachur et al. did report a 27%
increased odds of return to the ED within 3 days when diphen-
hydramine was used with a DRA rather than a DRA alone [2].
The incidence of extrapyramidal side effects with dopa-
mine receptor antagonists is not known. In Kabbouche et al.,
patients received prochlorperazine and IV fluids, and no side
effects were reported [1]. Trottier et al. describe a cohort of 48
pediatric patients with migraine who received
prochlorperazine and diphenhydramine in the ED setting.
Despite co-administration of diphenhydramine, the rate of
definite akathisia was 5% [6].
Serotonin Antagonists
Ondansetron is a common anti-nausea medication that is used
in the ED for which migraine is the 5th leading indication
[15]. It is reportedly given to 21% [2] of pediatric patients
seen in the ED for migraine and is commonly administered
in combination with analgesics or in place of dopamine recep-
tor antagonists. There is a paucity of studies that describe its
use as monotherapy for the abortive treatment of migraine.
Bachur et al. compared the return visit rate for patients who
received DRA versus ondansetron and did not identify a sta-
tistically significant difference [2].
Page 3 of 6 15
Anti-seizure Medications
Valproic acid and its derivatives are commonly used in the
pediatric and adult populations for preventative and abortive
treatment of migraine; however, the most recent pediatric
guidelines published by the AAN do not recommend its use
for either [7, 16]. They do not have an FDA indication for
abortive treatment for migraine in children or adults.
Notably, no known studies have been published that compare
the use of VPA to other traditional abortive medications. One
study reported that VPA is used as commonly as 75% as a
second line agent in the ED [13]. In the inpatient setting, VPA
is administered in 31% of migraine patients [10].
Reiter et al. was the first group to publish on the use of IV
VPA in the abortive treatment of pediatric migraine and re-
ported 47% of patients had a > 50% decrease in pain score.
The results of this study were potentially confounded by the
co-administration of IV dexamethasone and/or ondansetron
[17]. In 2015, Sheridan et al. described their cohort of 12
patients with a diagnosis of headache who had received intra-
venous VPA as a second-line treatment in the emergency de-
partment at 1 of 2 tertiary care centers. The mean pain reduc-
tion after VPA administration was 36% [5].
In 2018, Zafar et al. published a protocol for continuous
intravenous valproate as a new approach to abortive treatment.
Continuous administration of 1 mg/kg/h followed a typical
loading dose of 20 mg/kg IV. Infusion was then titrated to a
goal serum level of 80–100 mcg/mL. In their population of 83
pediatric patients with status migrainosus who had failed
home treatment as well as an initial IV treatment of ketorolac,
metoclopramide, and diphenhydramine, 66% had complete
resolution of pain, and an additional 5% had 50–99% reduc-
tion in pain. In those attaining headache freedom, 76%
achieved this by 24 h from initiation of infusion [18].
Steroids
The most common steroid used for treatment of migraine is
dexamethasone. In the adult literature, there is inconsistent
evidence to support the use of corticosteroids to reduce recur-
rence following discharge from the emergency department
[19, 20]. Its use in the pediatric population is unclear.
A paper published in Headache by Orr et al. described the
use of dexamethasone in an algorithm for migraine treatment
in an infusion center, which has a population similar to an ED.
Treatment protocol consisted of IV fluids, ketorolac, and
prochlorperazine versus metoclopramide followed by VPA
or dexamethasone, which was given at provider discre-
tion. Patients who were not given dexamethasone were
associated with 80% increased odds of treatment success
[21]. It is possible this reflects a selection bias for pa-
tients with refractory migraine.
 15 Page 4 of 6
Anesthetics
Ketamine Ketamine is an NMDA receptor selective antago-
nist. By blocking the NMDA receptor, it inhibits the excitato-
ry effects of glutamate, which is implicated in central sensiti-
zation and cortical spreading depression of migraine [22]. Use
of ketamine has been described primarily in the adult litera-
ture. The most recent studies by Lauritsen et al. and Pomeroy
et al. describe the use of ketamine infusions for chronic mi-
graine. Lauritsen et al. demonstrated a decrease in pain score
to less than 3 for all 6 patients with a mean time to effect of
44 h [23]. Pomeroy et al. demonstrated that 75% were re-
sponders, defined as 2-point reduction from admission head-
ache pain score, but only 23% had sustained response at first
follow-up visit [24].
At the time of this writing, there is a single study in the
pediatric population. Published in Pediatric Neurology in
2019, Turner et al. describe a cohort of 34 patients who pre-
sented to the ED with status migrainosus and received intra-
nasal ketamine. Protocol for administration was serial dosing
of intranasal therapy every 15 min, up to 5 total doses. 74% of
patients were responders, defined as absolute pain score of 0–
3 or > 50% reduction in pain score. Benefit for responders was
seen as early as the first dose in 36%, but was seen in all by the
5th dose. At time of discharge, mean absolute pain scores for
responders and non-responders was 1.4 vs 7.3, respectively
(p ≤ 0.001) [25•]. The sustained benefit of ketamine has not
been studied in the pediatric population.
Propofol Propofol is a sedative-hypnotic agent that achieves
its sedating properties by agonism at GABAA receptors.
Although the potential benefit of propofol for abortive treat-
ment of migraine, as well as nausea and vomiting, was first
described in 2000 in Headache [26], the anti-migraine prop-
erties are poorly understood. In 2012, Dhir et al. demonstrated
inhibition of cortical spreading depression following intraper-
itoneal administration of propofol hemisuccinate, a prodrug of
propofol, in a mouse model [27]. Proposed mechanisms of
action for anti-migraine effects are antagonism at NMDA re-
ceptor and voltage-gated calcium channels.
There have been 2 published studies from the same insti-
tution on the use of propofol in pediatric migraine. In 2012,
Sheridan et al. performed a retrospective cohort study com-
paring the effectiveness of propofol versus standard treatment
of NSAID, diphenhydramine, and prochlorperazine for a total
of 14 ED patients. The mean pain reduction was 80% for
propofol and 61% for standard therapy (p = 0.02). There was
no difference in length of stay or return ED visit within 24 h
[28].
In 2018, Sheridan et al. then conducted a prospective ran-
domized control trial comparing the effectiveness of propofol
versus standard therapy of ketorolac, diphenhydramine, and
DRA, of which most received metoclopramide due to national
Curr Neurol Neurosci Rep (2020) 20:15
shortage of prochlorperazine. Sixty-six patients aged 7–
19 years with a diagnosis of migraine and pain score of ≥ 6
were included. There was no significant difference for the
percent or absolute pain reduction; however, significantly
more patients experienced rebound headache at 24 h follow-
up in the standard therapy (67%) versus propofol (25%) group
(p = 0.01). There was no significant difference in length of
stay [29]. Additional studies are needed to confirm non-
inferiority.
Peripheral Nerve Blocks
Peripheral nerve blocks (PNBs) are a procedure performed by
child neurologists and pain specialists as an abortive treatment
for migraine in the outpatient, ED, or inpatient settings.
Injection of an anesthetic in proximity to the greater and lesser
occipital nerves, as well as other sensory nerves of the face,
modulates the trigeminal nucleus caudalis, which is pivotal in
the central sensitization of migraine. In 2016, a survey of
specialists who refer or perform PNBs was conducted, which
highlighted the variability seen in the procedure. The most
common indications are status migrainosus and chronic mi-
graine. The most common anesthetic used is 0.5%
bupivacaine, but other concentrations of bupivacaine or vary-
ing concentrations of lidocaine with or without methylpred-
nisolone, triamcinolone, dexamethasone, or sodium bicarbon-
ate are also used. The injections are performed either unilat-
erally or bilaterally [30].
Gelfand et al. performed a retrospective chart review of 46
pediatric patients with headache, of which 76% had chronic
migraine, investigating the benefit of first-time unilateral
greater occipital nerve blocks, using combination 2% lido-
caine and methylprednisolone. Sixty-two percent of patients
with chronic migraine benefitted with 35% of those reporting
significant benefit, described as > 1/3 improvement in dura-
tion, frequency, or intensity of migraine or documented “sig-
nificant” improvement for at least 1 month. For all patients,
mean latency of onset was 4.7 days with a mean duration of
benefit of 5.4 weeks [31].
In 2018, Puledda et al. conducted a retrospective chart re-
view of 205 pediatric patients receiving first-time or repeat
unilateral greater occipital nerve blocks, consisting of 1% li-
docaine and methylprednisolone, for a total of 458 proce-
dures. Follow-up data was available for 78% (n = 159) of pa-
tients, and of these, 79% had chronic migraine. Improvement
in pain, defined as > 1/3 decrease in frequency or intensity or
documentation of improvement, was seen in 68% of patients
with chronic migraine. Ten percent had sustained headache
freedom at 3 weeks post-procedure. For all patients, mean
duration of benefit was 9 weeks [32•]. A prior survey [30]
reported concern for diminished response with repeat injec-
tions, but this study did not investigate benefit for first time
versus repeat injections.
Curr Neurol Neurosci Rep (2020) 20:15
Dihydroergotamine
Dihydroergotamine (DHE) is a potent vasoconstrictor due to
agonist effect at serotonin receptors, primarily 5HT1D. The first
pediatric study for use of DHE was by Linder [33] in 1994;
however, continued research in the pediatric population has
been limited. Variety in the initial and incremental dosing of
DHE and type of access exists [3, 33, 34] in the published DHE
protocols, but in general, the medication is administered every
8 h, making it more appropriate for inpatient treatment. Rates of
use for inpatient encounters vary from 3 to 59% [2, 10].
Kabbouche et al. described a cohort of 32 patients who
were admitted for IV DHE treatment of pediatric migraine.
Treatment success, defined as headache freedom at discharge,
was achieved in 74% of patients. It was noted that a significant
decrease in headache pain occurred by dose 5 for most pa-
tients, but that 67% required 12–13 doses before achieving
headache freedom. Mean total dose administered was 7 mg,
and the average length of stay was 2.96 days. Treatment was
discontinued for 2 (6%) patients due to side effects [34].
Nelson et al. described a cohort of 124 unique patients with
145 admissions for IV DHE treatment of migraine with use of
Linder protocol. Although 63% of patients had improvement in
their headache, only 21% had complete resolution of pain. The
average number of doses administered for responders was 8.3,
while the non-responders received 7.2 doses (p = 0.002).
Duration of headache and use of prophylactic medication was
not statistically significant between the responders and non-re-
sponders, but the presence of a comorbid diagnosis, which anx-
iety and depression were the most common, was statistically
significant between the 2 groups (p = 0.034). The average length
of stay was 3.7 days. Eighteen patients required re-admission
within 1 week for additional headache treatment, but it is unclear
how many of these patients were initially responders. At follow-
up, only 29% of responders reported sustained benefit for fre-
quency or intensity of migraine [35]. Additional research is nec-
essary to standardize DHE protocols for maximal patient benefit.
Case Conclusion
In the ED, the patient received appropriate treatment for mi-
graine. She was given a migraine cocktail consisting of IV
normal saline bolus 1 L, ketorolac 30 mg, prochlorperazine
10 mg, and diphenhydramine 50 mg with improvement in
headache from an 8 to 4 out of 10. Valproate sodium
1000 mg IV was then administered with subsequent resolution
of migraine. She was discharged on a divalproex sodium taper
of 1000 mg twice daily for 3 days followed by 500 mg twice
daily for 3 days. She was seen in clinic for follow-up 4 weeks
later without any interval migraine. Our goal at our institution
is headache freedom prior to discharge, which was achievable
with our ED migraine protocol.
Page 5 of 6 15
Conclusion
This paper is a review of recent literature on the abortive
treatment of pediatric migraine in the emergency department
and inpatient settings, and there are several notable recent
advances. Treatment protocols in the ED can improve out-
comes by decreasing pain scores more efficiently and
preventing admissions. Continuous infusion is a novel ap-
proach to treatment with VPA. Ketamine, propofol, and pe-
ripheral nerve blocks have the potential to be quicker treat-
ments than multi-day admission for dihydroergotamine. Two
shortcomings of current literature is the focus on comparing
medications in isolation as they are rarely used that way and
treatment success is only rarely defined as headache freedom.
Randomized control trials continue to be rare in this patient
population but are necessary to confirm if these treatment
regimens are effective.
Compliance with Ethical Standards
Conflict of Interest The authors declare that they have no conflict of
interest.
Human and Animal Rights and Informed Consent This article does not
contain any studies with human or animal subjects performed by any of
the authors.
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