CHILDHOOD AND ADOLESCENT HEADACHE (S EVERS, SECTION EDITOR)
Medication Overuse in Children and Adolescents
Amy A. Gelfand & Peter J. Goadsby
Published online: 5 June 2014
#Springer Science+Business Media New York 2014
Abstract Medication overuse is not uncommon among chil-
dren and adolescents with primary headache disorders. Med-
frequency and reduced effectiveness of acute and preventive
medications. These issues probably exist in children. While
withdrawal of overused medications is generally recommend-
ed, it may not result in improved headache frequency in all
patients. This review summarizes what is known about
predicting the response to medication withdrawal. Strategies
for managing children and adolescents with medication over-
use are also offered.
Medication overuse in patients with primary headache disor-
ders is problematic on several fronts:
of acute headache medications by adults is associated
with the transformation of a migraine from episodic to
chronic . There is concern this may also be the case in
children . In adolescents with chronic daily headache,
without further definition, medication overuse is associated
with chronic daily headaches occurring even eight years
later . The pathophysiology underlying how medication
overuse can lead to increased headache frequency is not
2) Potential to make preventive medications less effective:
Medication overuse has been associated with lower effi-
cacy of migraine preventive medication , and with-
drawal may bring about a return of preventive efficacy
reverses upon medication withdrawal.
3) Potential for dependence and central side effects: Barbi-
turates and opioids have the potential for inducing a
patient’s tolerance and dependence. Their central side
effects include sedation and mental fogginess which are
particularly problematic in children as school perfor-
mance can be impacted.
4) Potential for opioids to reduce triptan effectiveness: It is
triptan use (e.g., rizatriptan) reduced response rates in
patients with a moderate or severe headache at baseline.
Interestingly, placebo responses were not different .
The frequency of use that constitutes medication overuse
depends on the type of medication. Barbiturate use even four
days a month is associated with progression to chronic mi-
graine in adults . Opioid, ergotamine, and triptan overuse
are defined as use on ten or more days per month in the
preceding three months, while for non-specific analgesics
the definition is use on at least 15 days per month in the
preceding three months [8••]. These frequency limits are
A. A. Gelfand (*):P. J. Goadsby
UCSF Headache Center, 1701 Divisadero St. Suite 480,
San Francisco, CA 94115, USA
P. J. Goadsby
A. A. Gelfand
UCSF Division of Child Neurology, San Francisco, USA
P. J. Goadsby
NIHR-Wellcome Trust Clinical Research Facility,
King’s College London, London, UK
Curr Pain Headache Rep (2014) 18:428
ten day rule for opioids was supported.
Historically, the diagnosis “medication overuse headache”
has required there be improvement in headache frequency
after medication withdrawal. Therefore, the diagnosis could
only be made in retrospect. This was difficult to apply practi-
cally and, therefore, in the 2013 International Classification
for Headache Disorders, Third Edition [8••] (ICHD-III beta)
the criteria no longer require that the headache developed or
worsened during medication overuse or that it improved upon
withdrawal of medications.
The most recent diagnostic criteria for medication overuse
headache are [8••]:
A. Headache occurring ≥15 days per month in a patient with
a pre-existing headache disorder.
B. Regularoveruse for>3monthsof oneormoredrugstaken
for acute and/or symptomatic treatment of headache.
C. Not accounted for by another ICHD-3 diagnosis.
Nevertheless, the term “medication overuse headache”
remains problematic as it implies that the medications are
causing the frequent headache. While in some individuals
medication overuse can lead to increased headache frequency
and discontinuing the medications can reduce headache fre-
quency, this is not the case in all individuals overusing
medications. In some individuals increasing headache fre-
quency is due to worsening of the primary headache disorder
and increased use of acute medications is simply a mirror of
clinical progression. Withdrawing the medications in these
situations may not result in diminished headache frequency
since the medications are not causative. Lack of improvement
after medication withdrawal has been seen in both adults and
children with medication overuse [9••, 10••, 11]. Moreover,
onlyabouta thirdofpeoplewhooveruse medicationsdevelop
frequent headache, implying there may be an innate genetic
implying causation the term “medication overuse” in this
paper will be used to refer simply to the arithmetic overuse
of acute medications (e.g., use of triptans more than ten days
How Common is Medication Overuse in the Pediatric
The rate of chronic migraine among U.S. adolescents is
0.79 % when those with medication overuse are excluded
and 1.75 % when they are included . The current ICHD-
III (beta) criteria for chronic migraine allows for a chronic
migraine diagnosis even in the presence of medication over-
use; this suggests that over half of U.S. adolescents with
chronic migraine also overuse acute headache medications.
varies from 21-60 % of those with chronic primary headache
disorders [9••, 11, 14–17]. When we examined medication
overuse data as published  it appears to be more common
among girls with chronic daily headaches than boys (48 % vs.
28 %, p=0.002). Medication overuse may be less common in
children and adolescents with “new daily persistent headache”
(NDPH) as compared to other headache disorders, particularly
chronic migraine. In one study 8.7 % of those with NDPH had
medication overuse compared to 33.3 % of those with chronic
migraine and 18.2 % of those with a chronic tension-type
headache . Of the 40 pediatric patients in that study with
medication overuse the majority (n=31, 77.5 %) had chronic
migraine (previously transformed migraine) .
What Types of Medications are Being Overused
in the Pediatric Population?
In adults there has been a temporal trend in the types of acute
headache medications being overused. Between 1990 and 2005
the proportion of patients with ergotamine overuse fell while the
proportion with triptan overuse rose, likely reflecting the in-
creased use of triptans over that period . Overuse of non-
specific analgesics is most common in adults overall  and
forty-two pediatric chronic daily headache patients with medi-
cation overuse more than half were overusing nonsteroidal anti-
inflammatory drugs (NSAIDs), about a quarter acetaminophen,
and only 12 % were overusing prescription medications .
More data are needed to clarify which types of medications
children and adolescents are overusing. The information is im-
portant prognostically as in adults certain medication classes
seem more likely to lead to migraine progressing from episodic
to chronic. Barbiturate-containing compounds seem most likely
to lead to migraine progression (OR 2.1, 95 % CI 1.3-3.1) with
opioids also being clearly problematic (OR 1.98, 95 % CI 1.4-
CI 0.9-1.7). Overall, NSAIDs were not associated with progres-
sion (OR 0.85, 95 % CI 0.6-1.2) and, in fact, NSAID use less
than ten days per month appeared to be protective .
How Does Medication Overuse Influence Headache
Not every patient with medication overuse improves after
the medication overuse itself is not necessarily driving the
headache frequency in all patients. It remains possible that
medication overuse produced a change in the central nervous
system of susceptible individuals. Nonetheless, it is important
428, Page 2 of 6 Curr Pain Headache Rep (2014) 18:428
to counsel patients that while a reduction in acute medication
intake is prudent, it may not be sufficient to induce symptom-
atic improvement. For example, in one pediatric study
discontinuing the overused medication(s) led to improvement
to predict among all headache patients who are arithmetically
overusing acute medications, in which ones the medication
use is playing a causative role. This would be particularly
useful in children as their headache frequency would improve
after withdrawal of overused medication and they would not
need to be exposed to more aggressive interventions.
Similarly it would be helpful to know in advance which
patients have a primary headache disorder that is problematic
in and of itself and the overused acute medications are simply
“along for the ride” and not causative. These patients should
be targeted early for more aggressive and comprehensive
interventions. However, at this time there is no clinical way
to distinguish the pediatric patients with medication overuse
who will respond to withdrawal of acute medications from
those who will not. Gene expression patterns do appear to
differ and could potentially beused in the futureasa biomark-
er to predict the response to treatment [9••].
drug withdrawal demonstrated a decreased gray matter vol-
ume in the midbrain (periaqueductal gray matter and nucleus
cuneiformis) whereas those who did not improve did not have
a similar reduction [10••]. More importantly for predicting
treatment response, decreased gray matter volume at baseline
in the orbitofrontal cortex was correlated with decreased like-
lihood of improvement after withdrawal [10••]. In addition,
impairment in orbitofrontal task performance on neuropsy-
chological evaluation is associated with poor prognosis
among adult migraine patients with medication overuse
[21••]. In the future perhaps assessing a child or adolescent’s
genomic expression pattern, orbitofrontal cortex structure
al from overused acute medications.
How Should Medication Overuse in Children
and Adolescents be Treated?
Certainly this is an area of much needed research. Published
evidence in the pediatric population is quite limited.
Strategies to Address Medication Overuse
A Course of Naproxen Sodium
In a small randomized trial of adults with chronic migraine,
60 % of whom were overusing triptans at baseline, a per
protocol analysis of 500 mg of naproxen sodium used daily
acute medication use [22•]. Italso led to a significant decrease
in migraine headache days (mean 16.4 (SD 1.9) days at
baseline compared to 6.2 (SD 4.0) at one month). It is worth
noting, however, that the drop-out rate in the naproxen group
was high. Nonetheless, the observed headache benefit did
continue in months two and three when the naproxen sodium
was used as needed up to 14 days per month. Disability from
migraine, as measured by a MIDAS score, was also signifi-
months, p<0.05). Those randomized to use combined
sumatriptan-naproxen daily for a month also had a reduction
in migraine days in the first month but this effect did not
continue into the subsequent months with as needed use.
A similar strategy of daily naproxen for a month followed
by as needed use could be used for children and adolescents
with chronic migraine and medication overuse in an effort to
reduce headache days while simultaneously aiming to reduce
overuse ofother acute medications. Supporting thispracticeis
a small placebo-controlled trial suggesting naproxen sodium
may be useful for episodic migraine prevention in adolescents
 and multiple trials of naproxen as a migraine preventive
in adults [24–28].
Greater Occipital Nerve Injection
When naproxen is contra-indicated or insufficient, an injec-
region around the greater occipital nerve is another treatment
option. In an open-label study these injections appear to be
primary headache disorders . Importantly, the odds of
benefit are not reduced in the setting of medication overuse
(OR 1.1, 95 % CI 0.3-4.5) . Similarly, in an open-label
adult study of greater occipital nerve injections for chronic
primary headache disorders the presence of medication over-
use did not predict poor treatment response . The mean
latency of onset to benefit in the pediatric study was 4.7 days
(SD 2.3). Thus, if the child’s headache disorder begins to
improve in the days following the injection they may be able
to begin decreasing the overuse of acute medications without
further intervention. Given the benign nature and excellent
tolerabilityofthese injectionsitisworthwhile consideringthis
treatment before progressing to more aggressive options.
A Course of Intravenous Dihydroergotamine
We admit these children for a course of intravenous dihydro-
ergotamine (DHE) if these initial measures are not enough.
We follow a published DHE protocol that has been used in
adults with chronic primary headache disorders . If barbi-
turate or opioid overuse is present we withdraw these
Curr Pain Headache Rep (2014) 18:428Page 3 of 6, 428
medications on the first day of admission and spend the first
several days treating the patient with intravenous fluids, anti-
emetics and NSAIDs as needed for headache and nausea
while providing clonidine regularly for opioid withdrawal or
phenobarbital for barbiturate withdrawal. Conducting the
withdrawal in the inpatient setting allows for closer monitor-
ing and the opportunity to provide the child and the family
with additional support. Once withdrawal symptoms have
passed we begin the DHE treatment. When there is triptan
to admission. There is some evidence in adults that headaches
from triptan withdrawal may be shorter and less severe than
triptan to wash out before starting DHE treatment.We would
also discontinue combination analgesics or acetaminophen
several days prior to starting the DHE course.
Treatment Approach Following Withdrawal of Overused
Opioids and barbiturate-containing compounds can be cate-
gorically discontinued and their further use discouraged.
NSAIDs and triptans are good mainstays for acute headache
treatments along with anti-emetics if needed for nausea. Do-
pamine receptor antagonists, such as chlorpromazine or
prochlorperazine, are usefulalternatives, particularly for those
with significant nausea or a contra-indication to triptans.
use can act as a migraine preventive and decrease migraine
frequency. Acute intermittent use of NSAIDs may also have a
disease-modifying effect. In adults NSAID use less than ten
days per month appears to be protective against progressing
from episodic migraine to chronic migraine . Moreover, in
a recent adult pilot study naproxen use up to 14 days per
month was found to decrease the number of migraine head-
ache days at three months and to decrease the number of
headache attacks as soon as one month into treatment [32•].
Given the evidence, it seems unnecessary, and perhaps even
counterproductive, to limit significantly the number of days a
child uses naproxen, at least from the standpoint of concern
for medication overuse headache or progression of episodic
migraine into chronic migraine. Limiting frequency due to
renal or gastrointestinal concerns may be appropriate.
Triptans have been extensively studied in children and
adolescents and there are positive randomized placebo-
controlled trials for sumatriptan nasal spray, almotriptan,
rizatriptan and zolmitriptan nasal spray and tablets [33–40].
Almotriptan (Axert) and rizatriptan (Maxalt) are FDA-labeled
for treatment of acute migraine in ages 12-17 and 6-17 years,
respectively. We generally limit triptan use to two days per
efficacy and a lower potential of recurrence within the first
twenty-four hours than using either agent alone . This
combination of medications has been studied in adolescents
with naproxen may also decrease the likelihood of developing
triptan overuse headache. Repeated exposure to triptans in
that appears to be blocked by co-administration of naproxen
. In a pilot study of adults who used a sumatriptan-naproxen
combination up to fourteen days per month for three months, a
frequency that would be thought of as triptan overuse, partici-
pants did not develop an increase in headache days. In fact, the
number of headache days at three months was lower than at
baseline, though the difference was not statistically significant
[32•]. Both using naproxen in isolation and sumatriptan/
naproxen in combination were associated with decreased use
of acute medications over the three months of therapy.
Certainly the overarching goal in managing a child with
medication overuse headache is to decrease the number of
headache days the child experiences. Optimizing their acute
medications is, therefore, only one piece of the puzzle. The
long-term treatment strategy is to find an effective preventive
regimen so that acute medications are not needed as frequent-
ly. The preventive regimen will likely consist of certain life-
style modifications, such as regular sleep, as well as migraine
preventive medication. While headache frequency is being
brought under control there may be a period of time during
which the child can not treat every single headache with a
prescription medication. Even ifpain ispresent,limitingacute
medication use (other than naproxen) may be necessary for a
period in order to avoid medication overuse headache and to
often needed to explain this to families, which is quite under-
with coping techniques, such as biofeedback or counseling,
are sometimes appropriate to help the patient and family get
through this transitional stretch.
Medication overuse is relatively common in children and
adolescents, particularly among those with chronic migraine.
Not every pediatric migraine patient who overuses acute
headache medications will respond to medication withdrawal.
Thus, it would be useful to be able to predict who will
respond.Similarly, not all acute medications are equallylikely
to cause the difficulties associated with medication overuse.
Based on adult data, barbiturate-containing compounds seem
to be most problematic in this regard, followed by opioids.
Both should be avoided in children. The potential for frequent
triptan use to become problematic may be lessened through
co-administration of naproxen. It is unclear that NSAIDs in
general, and naproxen sodium in specific, can cause
428, Page 4 of 6Curr Pain Headache Rep (2014) 18:428
medication overuse headache. Naproxen sodium may even be
protective and its use could decrease headache frequency.
Optimizing preventive therapy is key in helping children and
adolescents stop overusing acute medications, and greater
roles in providing short-term and medium-term headache
control while longer-term preventive therapies take effect.
Compliance with Ethics Guidelines
Conflict of Interest
NIH/NINDS (K12NS001692) and the UCSF Center for Translational
Science Institute. She has received honoraria from Journal Watch Neu-
rology and personal compensation for legal consulting.
Dr. Peter J. Goadsby is on the boards of Allergan, Colucid, MAP
pharmaceuticals, Merck, Sharpe and Dohme, eNeura, Autonomic Tech-
nologies Inc, Boston Scientific, Eli-Lilly, Medtronic, Linde gases,
for Pfizer, Nevrocorp , Zogenix, Impax, Zosano and Dr. Reddy, and has
been compensated for expert legal testimony. He has grant support from
MAP, MSD, Allergan, and Amgen. He has received honoraria for speak-
ing from Pfizer and Allergan, and payment for editorial work from
Journal Watch Neurology and for developing educational materials for
the American Headache Society.
Dr. Amy A. Gelfand receives grant support from
Human and Animal Rights and Informed Consent
not contain any studies with human or animal subjects performed by any
of the authors.
This article does
Papers of particular interest, published recently, have been
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