Review Article

Risk Factors for and

Address correspondence to
Dr Richard B. Lipton, Albert
Einstein College of Medicine,

1300 Morris Park Avenue,
Room 332, Rousso Building,
Department of Neurology,
Bronx, NY 10461,
Richard.lipton@einstein.yu.edu.
Relationship Disclosure:
Dr Lipton serves as a consultant
for and receives personal
compensation for speaking
engagements and paid travel
accommodations/meeting
expenses from Alder
Biopharmaceuticals Inc;
Allergan, Inc; Autonomic
Technologies, Inc; Avanir
Pharmaceuticals, Inc; Boston
Scientific Corporation; Bristol-
Myers-Squibb Company;
CoLucid Pharmaceuticals, Inc;
Dr. Reddy’s Laboratories;
electroCore Medical, LLC;
eNeura Inc; Labrys Biologics;
Merck & Co, Inc; Novartis AG;
Teva Pharmaceutical Industries
Ltd; and Vedanta Biosciences.
Dr Lipton receives personal
compensation for speaking
engagements and paid travel
accommodations/meeting
expenses from the American
Headache Society. Dr Lipton
receives honoraria from
Informa PLC and owns stock or
stock options in eNeura Inc.
Unlabeled Use of
Products/Investigational
Use Disclosure:
Dr Lipton discusses the
unlabeled/investigational use
of acebutolol, candesartin,
captopril, divalproex sodium,
lisinopril, metoprolol, nadolol,
Petasites hybridus, propranolol,
timolol, and topiramate for the
treatment of chronic migraine
and the use of naproxen,
naratriptan, and prednisone for
the acute treatment of migraine.
* 2015, American Academy
of Neurology.
1118 www.ContinuumJournal.com
Management of
Medication-Overuse
Headache
Richard B. Lipton, MD, FAAN
ABSTRACT
Purpose of the Review: This review focuses on patients with migraine who frequently
use acute medications.
Recent Findings: Chronic migraine and medication-overuse headache are common
in the general population and often coexist. According to new diagnostic criteria,
both diagnoses can be made for an individual patient. Evidence is slowly emerging
on the most appropriate management approach for both disorders.
Summary: Although the relationship of the primary headache disorder and the
pattern of overuse varies, medication-overuse headache is a secondary disorder attrib-
utable to the overuse of acute medications. While distinguishing chronic migraine and
medication-overuse headache may not always be possible, treatment approaches are
similar for the two disorders.
Continuum (Minneap Minn) 2015;21(4):1118–1131.
INTRODUCTION days per month for at least 3 months, and
Increasing use of acute treatments for 8 or more headache days per month
migraine has long been associated with linked to migraine by clinical features.
a worsening profile of headaches, although In previous editions of the ICHD, medi-
cation overuse excluded the diagnosis
the causal sequence is not always clear
of chronic migraine. In the recently re-
(Figure 12-1).1Y3 This article considers
vised edition, chronic migraine is divided
the evidence from epidemiologic studies
into forms with and without medication
and clinical trials that informs the diag- overuse. The patient in Case 12-1 meets
nosis and treatment of patients with mi- criteria for chronic migraine and medi-
graine who frequently consume acute cation overuse.4 This diagnosis does
medications for headache. A case-based not imply a causal relationship between
approach will be used to illustrate the the overused medication and the occur-
diagnostic and therapeutic challenges rence of frequent headache.
that arise in these patients (Case 12-1).
Based on the current edition of the POSSIBLE RELATIONSHIPS
International Classification of Head- BETWEEN MEDICATION USE
ache Disorders, Third Edition, beta AND HEADACHE FREQUENCY
version (ICHD-3 beta), the patient in The patient in Case 12-1 could also meet
Case 12-1 meets criteria for chronic criteria for medication-overuse headache
migraine (Table 12-1).4 She has a his- (Table 12-2). She has headaches 15 or
tory of migraine, 15 or more headache more days per month. She takes butalbital,
August 2015

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 KEY POINT
h Medication-overuse
headache is a secondary
disorder attributable to
the overuse of acute
medications. Chronic
migraine with medication
overuse is a primary
headache disorder.

FIGURE 12-1 Possible relationships of headache and medication use. This cyclic process begins
with headache, which leads to increased medication use; medication use
or withdrawal, which leads to increased headache; and medication overuse,
which leads to medication-overuse headache.

aspirin, caffeine 25 days per month and
experienced headache acceleration dur-
ing a period of increased medication use.
The diagnosis of medication-overuse head-
ache implies that the overused medica-
tion causes the headache. The distinction
between chronic migraine with medica-
tion overuse and medication-overuse
headache is subtle. The diagnostic issue
hinges on ICHD-3 beta criterion ‘‘D’’ for
chronic migraine and criterion ‘‘C’’ for
medication-overuse headache. Are her
headaches best accounted for by chronic
migraine or by medication-overuse
headache? Ultimately, this is a clinical
judgment. This distinction, although
important for headache nosology, is
not all that important from a clinical
perspective. Clinically, frequent head-
aches and medication overuse are prob-
lems to be addressed. If the overused
medication were tapered (gradually to
avoid barbiturate withdrawal) and the
headaches rapidly improved, the diag-
nosis of medication-overuse headache
would be favored. If the overused
medication were withdrawn and the
daily headaches persisted, the diagno-
sis of chronic migraine with medication
overuse would be favored. In either case,
diagnostic resolution based on clinical
course is imperfect and occurs only after
medication overuse resolves.
Medication overuse has at least four
possible relationships to headache ac-
celeration that are not mutually exclusive
in the patient in Case 12-1 and in other
patients (Figure 12-1).5 First, medication
overuse could be a response to increas-
ing headache frequency without playing
a causal role. That is, as patients experi-
ence more headaches, they may take more
medication to relieve their pain and
other symptoms. Second, medication use

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 Medication-Overuse Headache

Case 12-1
A 25-year-old right-handed woman was diagnosed with migraine without
aura at age 16. Until 1 year ago, she had headaches 2 or 3 days per month,
which were rapidly relieved with a combination butalbital, aspirin, caffeine
product. Over the past year her headaches had steadily increased in frequency,
and her use of butalbital, aspirin, caffeine had also increased. She presented
with headache 25 days per month, including 12 days per month of severe
headache. Her severe headaches were unilateral (right more often than left),
pulsatile, and associated with nausea and photophobia. They lasted 12 hours
each on average. The headaches often awakened her from sleep before
her alarm clock went off. They were quite severe if she slept late on the
weekends. Even on days when she had no headache, she found it painful to
brush her hair or wear a headband most days. Her scalp was tender on the
right, even when she had been headache free for 24 hours. Exacerbating
factors included menses and relaxation after stress. On severe headache days
she took 4 to 6 tablets of butalbital, aspirin, caffeine per day, and on less severe
headache days she took 2 tablets per day for a total of 25 days per month
of butalbital, aspirin, caffeine use. She took a tricyclic antidepressant several
years ago but discontinued it because of sedation and weight gain. Her mother
and sister also carried the diagnosis of migraine without aura. Her neurologic
examination, including fundi and visual fields, was entirely normal.
Her internist had sent her for an MRI, routine labs, thyroid function tests,
a Lyme titer, and an erythrocyte sedimentation rate, all of which were
normal. Her internist told her that she had rebound headache and asked her
to gradually taper the butalbital, aspirin, caffeine. The patient was unable
to do so, leading to the neurologic referral.
Comment. This patient has a 1-year history of worsening headache and
increasing medication use. An initial diagnosis of migraine is supported
by her pattern of pain and associated symptoms, her menstrual exacerbations,
and her positive family history. Secondary headache (other than
medication-overuse headache) is unlikely in light of the long history, the
normal examination, and negative diagnostic workup. Her scalp tenderness
represents allodynia, the experience of ordinarily nonpainful stimuli as
painful. The inability to comply with instructions to taper or discontinue the
overused medication highlights the need for a multimodal approach to
management that must include a biobehavioral approach, trigger avoidance,
discontinuation of the overused analgesic, an alternative acute medication
used no more than twice per week, a bridge therapy to reduce withdrawal
headaches, and initiation of a preventive medication to facilitate effective
withdrawal, compliance with the regimen, and improved long-term outcomes.

or withdrawal between dosages may be headache or headache attributable to

a trigger for recurrent headaches. Ex-
posure to or withdrawal from butalbital,
aspirin, caffeine products may initiate
attacks of the primary headache disorder
or make them more severe. When medi-
cation withdrawal triggers a preexisting
primary headache disorder, that process
is sometimes referred to as rebound
substance withdrawal. The morning
headaches experienced by the patient
in Case 12-1 likely represent end-of-
dosing-interval headaches, which occur
as medication wears off. Third, medi-
cation overuse may cause a de novo
secondary headache disorder known
as medication-overuse headache that

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 KEY POINTS
a h Medication overuse has
TABLE 12-1 ICHD Diagnostic Criteria for Chronic Migraine
at least four possible
A. Headache (tension-type-like and/or migraine-like) on Q15 days per month relationships to
for 93 months and fulfilling criteria B and C headache acceleration
that are not mutually
B. Occurring in a patient who has had at least five attacks fulfilling criteria
exclusive: (1) medication
BYD for migraine without aura and/or criteria B and C for migraine
overuse could be a
with aura
response to increasing
C. On Q8 days per month for 93 months, fulfilling any of the following: headache frequency
1. Criteria C and D for migraine without aura without playing a causal
role; (2) medication use
2. Criteria B and C for migraine with aura or withdrawal may be
3. Believed by patient to be migraine at onset and relieved by a triptan or a trigger for the primary
ergot derivative headache disorder;
(3) medication overuse
D. Not better accounted for by another ICHD-3 beta diagnosis
may cause a de novo
ICHD-3 beta = International Classification of Headache Disorders, Third Edition, beta version. secondary headache
a
Reprinted from with permission Headache Classification Committee of the International Headache
Society (IHS), Cephalalgia.4 B 2013 International Headache Society. www.ihs-classification.org/
disorder known as
_downloads/mixed/International-Headache-Classification-III-ICHD-III-2013-Beta.pdf. medication-overuse
headache; (4) a positive
feedback loop may be
present, with headache
is superimposed on the primary head- MEDICATION OVERUSE AND leading to medication
ache disorder.5 The term ‘‘medication MEDICATION-OVERUSE HEADACHE use, which in turn leads
overuse’’ describes medication-taking People with chronic migraine often en- to more headache and
behavior, while the term medication- gage in the behavior of taking too much escalating doses
overuse headache implies that the head- acute medication (medication overuse). of medication.
ache is attributable to the overused Table 12-2 shows ICHD-3 beta diag-
h If headaches accelerate
medication. Finally, a positive feedback nostic criteria for medication-overuse
in response to increasing
headache. Medication-overuse head-
loop may be present, with headache lead- medication use or
ache is operationally defined based on
ing to medication use, which in turn leads improve when the
quantities of medication taken, with di- overused medication is
to more headache and escalating doses
agnostic thresholds that vary with med- withdrawn, a diagnosis
of medication. Differentiating these pos-
ication class.4 Patient use of triptans, of medication-overuse
sibilities in individual patients is chal-
ergot alkaloids, combination analgesics, headache is supported.
lenging. If headaches accelerate in or opioids on 10 or more days per month
response to increasing medication use or h Medication-overuse
constitutes medication overuse. Patient headache is operationally
improve when the overused medication use of simple analgesics, including non- defined based on
is withdrawn, a diagnosis of medication- steroidal anti-inflammatory drugs quantities of medication
overuse headache is supported. One (NSAIDs), on 15 or more days per month taken, with diagnostic
problem with this approach is that the constitutes medication overuse. Finally, thresholds that vary with
diagnosis is assigned retrospectively, patient use of more than one medica- medication class.
after the disorder remits with medication tion for headache (eg, NSAIDS and
withdrawal. Moreover, since withdrawal triptans) on a total of 10 or more days
of the overused drug is very difficult to per month also constitutes medication
accomplish in practice without the use overuse.4
of preventive medication or other man-
agement approaches, the attribution of Epidemiology
decreasing headache frequency to the The population prevalence of medication-
withdrawal of the medication may not overuse headache usually ranges from
be entirely accurate. 1% to 2% with a 3:1 female to male

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 Medication-Overuse Headache
KEY POINTS
h The population
prevalence of
medication-overuse
headache usually
ranges from 1% to 2%
with a 3:1 female to
male preponderance.
Medication-overuse
headache is most
common in midlife and
less common in
children, adolescents,
and the elderly.
Medication-overuse
headache is more
common in persons of
low socioeconomic
status and higher body
mass index.
h In epidemiologic studies,
medication-overuse
headache and chronic
migraine associated with
medication overuse are
difficult to distinguish.
h The risk of chronic migraine
onset is elevated in
persons with higher
headache frequency and
greater disability; obesity,
snoring, allodynia,
depression, anxiety, and
a poor response to
acute treatment are
also risk factors.
h Opioids are associated
with a 44% increase
in the risk of chronic
migraine onset.
h Overuse of butalbital,
aspirin, caffeine treatment
is associated with a
more than 70%
increased risk of
headache progression,
particularly in women.
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a
TABLE 12-2 ICHD Diagnostic Criteria for Medication-Overuse Headache
A. Headache occurring on Q15 days per month in a patient with a preexisting
headache disorder
B. Regular overuse for 93 months of one or more drugs that can be taken for
acute and/or symptomatic treatment of headache
C. Not better accounted for by another ICHD-3 beta diagnosis.
ICHD-3 beta = International Classification of Headache Disorders, Third Edition, beta version.
a
Reprinted with permission from Headache Classification Committee of the International Headache
Society (IHS), Cephalalgia.4 B 2013 International Headache Society. www.ihs-classification.org/
_downloads/mixed/International-Headache-Classification-III-ICHD-III-2013-Beta.pdf.
preponderance.6 Medication-overuse head- modifiable risk factors were examined.
ache is most common in midlife and less The risk of chronic migraine onset is
common in children, adolescents, and the elevated in persons with higher head-
elderly. Medication-overuse headache is ache frequency and greater disability;
more common in persons of low socio- obesity, snoring, allodynia, depression,
economic status and higher body mass anxiety, and a poor response to acute
index. It is also associated with psychi- treatment are also risk factors.8
atric comorbidities, including depression Use of certain classes of acute med-
and anxiety, as well as sleep disturbance ication is associated with an increased
and smoking.6 In population studies, it risk of chronic migraine onset in persons
may be difficult to ascertain a history of with episodic migraine (Table 12-3).5
headache acceleration during a period In particular, opioids are associated with
of accelerated medication use. In epi- a 44% increase in the risk of chronic mi-
demiologic studies, medication-overuse graine onset.1 Barbiturate-containing an-
headache and chronic migraine associ- algesics were associated with a more than
ated with medication overuse are difficult 70% overall increased risk of chronic mi-
to distinguish. Chronic migraine without graine onset.1 In contrast with opioids,
medication overuse has a population the risk of chronic migraine onset with
prevalence of 1% to 2%.7 barbiturates was higher in women than
in men.1 These data show that overuse of
MEDICATION USE AND butalbital, aspirin, caffeine treatment
HEADACHE PROGRESSION is associated with headache progression,
As illustrated by the patient in Case 12-1, particularly in women.1,5 These data are
persons with episodic migraine may compatible with the hypothesis that
progress to chronic migraine. In the taking the wrong categories of medica-
large-scale epidemiologic American Mi- tion, particularly opioids and barbiturate-
graine Prevalence and Prevention (AMPP) containing analgesics, contributes to
Study, individuals with episodic migraine headache progression. Because taking
developed the new onset of chronic medication one year is associated with
migraine at the rate of about 2.5% per an increased risk of chronic migraine
year.1,8,9 Rates of progression are asso- onset the next, that temporal sequence
ciated with a number of risk factors. The supports a causal relationship. How-
AMPP Study examined features in per- ever, it is possible that clinicians chose
sons with episodic migraine one year that these classes of medication for reasons
influenced the onset of chronic migraine associated with a higher risk of headache
the next year. Both modifiable and non- progression, such as a more aggressive
August 2015
TABLE 12-3 Medications Used at Baseline That Predict the Onset aof Chronic Migraine in
Persons With Episodic Migraine Stratified by Gender

Females Females Males Males Overall

Unadjusted Adjusted OR Unadjusted Adjusted OR Adjusted OR
OR (95% CI) (95% CI) OR (95% CI) (95% CI) (95% CI)
Acetaminophen 1.0 (reference) 1.0 (reference) 1.0 (reference) 1.0 (reference) 1.0 (reference)
Nonsteroidal anti- 0.88 0.97 0.85 0.93 0.96
inflammatory drugs (0.62Y1.26) (0.67Y1.41) (0.46Y1.55) (0.46Y1.88) (0.69Y1.34)
Triptans 1.11 0.93 2.37 2.11 1.05
(0.76Y1.63) (0.62Y1.40) (1.20Y4.71) (0.97Y4.63) (0.73Y1.50)
Barbiturate 2.29 1.97 1.42 1.29 1.73
compounds (1.44Y3.64) (1.21Y3.23) (0.43Y4.72) (0.38Y4.37) (1.10Y2.73)
Opiates 1.74 1.28 3.48 2.76 1.44
(1.15Y2.63) (0.81Y1.97) (1.74Y6.96) (1.20Y6.38) (1.10Y2.08)
Isometheptene 0.94 0.85 1.64 1.60 0.93
compounds (0.41Y2.16) (0.36Y2.02) (0.38Y7.09) (0.34Y7.54) (0.44Y1.98)
OR = odds ratio; CI = confidence interval.
a
Modified with permission from Bigal ME, et al, Headache.1 B 2008 the Authors; B 2008 American Headache Society. onlinelibrary.wiley.com/
doi/10.1111/j.1526-4610.2008.01217.x/full.

biology characterized by more severe KEY POINTS

or treatment-resistant headaches (ie,
confounding by indication).
In addition, the risk of chronic mi-
graine onset varies with frequency of
medication use and the number of head-
ache days a patient experiences each
month.1,5 As days of barbiturate use in-
crease, the risk of chronic migraine onset
increases. This represents a kind of dose-
response curve for chronic migraine on-
set. Although NSAIDs and triptans are not
risk factors for chronic migraine onset
overall (Table 12-410,11), in patients with
higher frequency of episodic migraine
(10 to 14 headache days/month), as days
of medication use increase, so does the
risk of chronic migraine onset.
EFFECTS OF MEDICATION
WITHDRAWAL
Withdrawal of overused medications is
often associated with a striking decline
in both pain intensity and frequency of
headache in patients with migraine. With
educational interventions, 42% to 92% of
h The risk of chronic
patients with chronic migraine and med-
migraine onset varies
ication overuse revert to episodic mi- with frequency of
graine within 18 months; however, up medication use and the
to 41% of detoxified patients relapse number of headache
within the first year after withdrawal.12Y17 days a patient
Classic studies show that triptan with- experiences each month.
drawal over a 1-week period is associated h With educational
with a striking decline in both number interventions, 42% to
and average pain intensity of head- 92% of patients with
aches.12,13 Benefits of withdrawal are chronic migraine and
medication overuse
almost as striking for ergot alkaloids but
revert to episodic
much less impressive for simple and
migraine within
combination analgesics. 18 months; however,
Of the four mechanistic scenarios up to 41% of
presented in Figure 12-1, improvement detoxified patients
of headaches when an overused medica- relapse within the first
tion is withdrawn is not compatible with year after withdrawal.
the hypothesis that taking medication is
a consequence of frequent headache. It
is compatible with the other three hy-
potheses. If medication use increases
headache frequency, then reducing medi-
cation overuse should decrease it. If med-
ication overuse causes medication-overuse

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 Medication-Overuse Headache

KEY POINTS
h With certain acute
medications, particularly
opioids or
barbiturate-containing
medications, alterations
in pain-processing
pathways may render
the headache pain
continuous and no longer
responsive to withdrawal
of the offending drug,
even though the drug
may have contributed to
the progression of
headache over time.
h Preventive treatments
are taken on a daily
basis to reduce headache
frequency, duration,
and/or severity.
h Preventive medication may
facilitate the medication
withdrawal process.
TABLE 12-4 US Food and Drug AdministrationYApproved
Prescription Treatments for Management of Migrainea
b Acute Management of Migraine
Triptans (oral, nasal, injectable, transdermal): Almotriptan, eletriptan,
frovatriptan, naratriptan, rizatriptan, sumatriptan, zolmitriptan
Dihydroergotamine mesylate (tablets, nasal sprays)
Diclofenac potassium oral solution
b Prevention of Episodic Migraine
Propranolol (tablets, liquid)
Timolol (tablets)
Divalproex sodium extended release
Sodium valproate
Topiramate
Transcutaneous supraorbital neurostimulation (tSNS) headband
b Prevention of Chronic Migraine
OnabotulinumtoxinA injections
a
Data from Physician’s Desk Reference 2014,10 Robert T, www.helpforheadaches.com/articles/
2012/Migraine-Medications-Approved-FDA.htm.11

headache, withdrawal should result in migraine associated with medication over-

improvement. And if taking medication
is part of a positive feedback loop that
accelerates headache, then breaking the
feedback loop should reduce headache
frequency. However, with certain acute
medications, particularly opioids or
barbiturate-containing medications, al-
terations in pain-processing pathways
may render the headache pain contin-
uous and no longer responsive to with-
drawal of the offending drug, even though
the drug may have contributed to the
progression of headache over time.
PREVENTIVE TREATMENTS AND
MEDICATION OVERUSE
Preventive treatments are taken on a daily
basis to reduce headache frequency, du-
ration, and/or severity; they are part of
the treatment of frequent and disabling
migraine. An often-debated issue is the
role and optimal timing of preventive
medications in the setting of frequent
1124 www.ContinuumJournal.com
use.18,19 Some argue that the overused
medication should be discontinued be-
fore starting preventive treatment while
others believe that starting a preventive
medication facilitates the withdrawal pro-
cess. Hagen and colleagues20 conducted
a three-arm study randomly assigning pa-
tients to a control intervention, abrupt
withdrawal without preventive medica-
tion, and abrupt withdrawal of the over-
used medication with prevention. Decline
in headache days was greatest in the
group undergoing withdrawal with a
preventive medication, intermediate in
the group undergoing withdrawal with-
out a preventive medication, and least
in the control group. These findings sup-
port the idea that preventive medication
may facilitate the medication withdrawal
process.20 In randomized trials of persons
with chronic migraine, both topiramate
and onabotulinumtoxinA resulted in
decline in headache frequency and
August 2015

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 KEY POINTS
reduction in the use of acute medications, provokes headache, sleep hygiene can h Preventive medications
even in the absence of specific instruc- be helpful. Reducing other exacerbating should be part of the
tions about medication withdrawal.21Y25 factors, such as obesity and other forms initial treatment of patients
These results support the hypothesis that of chronic pain, can also be beneficial. with migraine and
preventive medications should be part Optimal use of acute treatment varies medication overuse.
of the initial treatment of patients with from patient to patient.18,19 Acute treat- h From a therapeutic
migraine and medication overuse.26 ments are most effective when taken perspective, the
early in the attack while pain intensity is approaches to chronic
TREATMENT still mild; for patients with infrequent migraine with
Overview and headaches that tend to become more medication overuse and
Nonpharmacologic Approaches severe over time, treating early is usually medication-overuse
From a therapeutic perspective, the ap- the best approach. For patients with headache are
proaches to chronic migraine with medi- frequent headaches, reaching for med- virtually identical.
cation overuse and medication-overuse ication at the first sign of an attack can h The goals of treatment
headache are virtually identical. Although be counterproductive. Patients some- include eliminating or
randomized trials have assessed the ben- times treat mild headache or anticipatory minimizing the acute
efits of some preventive treatments in anxiety regarding an impending head- treatment that is being
these patients, systematic data on mul- overused and reducing the
ache. If the severe headache does not
tifactorial approaches to treatment are headache frequency and
occur, the patient may conclude, with
extremely rare. The goals of treatment severity. Once medication
tremendous relief, that the medication
overuse is eliminated, the
include eliminating or minimizing the averted the headache. This may rein- long-term goals are to
acute treatment that is being overused force the false belief that medication maintain the improvement
and reducing the headache frequency aborted the headache in some cases. and to prevent relapse.
and severity.3 Once medication overuse To break a behavioral chain of medi-
h Modifying the
is eliminated, the long-term goals are to cation overuse, it is often helpful to offer pattern of medication
maintain the improvement and to pre- alternative nonpharmacologic interven- overuse requires
vent relapse. Treatment of these disor- tions, including practicing a relaxation both a behavioral
ders usually requires nonpharmacologic method, rest in a quiet dark room, and and a pharmacologic
intervention, modifications of acute treat- applying cold compresses or pressure intervention.
ment, and effective preventive treatment. to the painful areas.
h Nonpharmacologic
Nonpharmacologic treatment strategies approaches with
include education, lifestyle management, Preventive Treatment demonstrated efficacy
and trigger avoidance. Modifying the pat- Most patients with migraine and medi- for migraine include
tern of medication overuse requires both cation overuse will benefit from preven- cognitive-behavioral
a behavioral and a pharmacologic inter- tive treatment. No firm rules exist to help therapy, relaxation
vention. A headache diary can be used to clinicians decide which preventive agent techniques,
identify headache triggers and to mea- should be chosen. Studies for the pre- and biofeedback.
sure the frequency as well as the intensity ventive treatment of chronic migraine h For patients with
of attacks. In the context of medication are strongest for onabotulinumtoxinA and infrequent headaches
overuse, diaries provide an accurate re- topiramate.21Y23 Preventive medications that tend to become
cord of patterns of acute medication use. are often beneficial, even in patients more severe over time,
Nonpharmacologic approaches with who overuse acute migraine agents treating early is usually
demonstrated efficacy for migraine (Table 12-5). The effectiveness of a pre- the best approach. For
include cognitive-behavioral therapy, re- patients with frequent
ventive agent can be determined after
laxation techniques, and biofeedback. headaches, reaching for
at least 2 to 3 months at a therapeutic
medication at the first
Cognitive-behavioral therapy can help level.27,28 For onabotulinumtoxinA, two sign of an attack can be
patients manage factors that precipitate or three cycles of treatment may be counterproductive.
or aggravate migraine and address issues needed to get full benefits. Patients of-
of mood or stress. As disrupted sleep ten fear that preventive treatment is a

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 Medication-Overuse Headache

TABLE 12-5 Management Approaches for Medication-Overuse Headache

Overused Acute Treatment Options

Treatment Tapering Strategy for the Overused Medicationa Bridge Therapya
Butalbital Gradual taper Add a triptan or a nonsteroidal Consider a
combinationb anti-inflammatory drug (NSAID)c long-acting triptan
(eg, naratriptan)
Long-acting NSAID
c
(eg, naproxen)
Steroid taper (eg, prednisone
c
60 mg/d for 3 days)
Butalbital Abrupt taper Substitute phenobarbital Consider a long-acting triptan
combinationb and taper Long-acting NSAID if needed
Add a triptan or an NSAIDc
Opioid Gradual taper Add a triptan or an NSAIDc Consider a long-acting triptan
Long-acting NSAID if neededc
Triptan/ergot Abrupt or gradual Add an NSAIDc Long-acting NSAID or
alkaloid a steroid taperc
NSAID Abrupt or gradual Add a triptan Consider a long-acting triptan
a
The acute treatment option and the bridge therapy should be compatible and from different classes.
b
Butalbital combination products including an analgesic (aspirin or acetaminophen) and caffeine.
c
In the absence of aspirin or an NSAID.

KEY POINTS
h Patients often fear that
preventive treatment is
a lifelong commitment
and should be told that
the need for prevention
will be reassessed
several times per year;
patients who respond to
preventive approaches
may be able to taper or
discontinue therapy
after 6 to 12 months of
successful treatment.
h Patients with chronic
migraine with or without
medication overuse
often require long-term
treatment as relapse
tends to be high,
especially in those with
long-standing disease.
lifelong commitment and should be told
that the need for prevention will be re-
assessed several times per year; patients
who respond to preventive approaches
may be able to taper or discontinue ther-
apy after 6 to 12 months of successful
treatment. However, patients with chronic
migraine with or without medication
overuse often require long-term treatment
as relapse tends to be high, especially in
those with long-standing disease.12,13
The American Headache Society and
the American Academy of Neurology
(AAN) have developed guidelines for the
preventive treatment of migraine, not
specific for chronic migraine or medi-
cation overuse.27,28 (Refer to Appendix A
and Appendix B for a summary of the
AAN’s evidence-based guidelines for
clinicians.) Drugs with at least two high-
quality double-blind studies were given a
Level A rating. Agents receiving this rating
for preventive treatment of episodic
migraine include divalproex sodium,
topiramate, metoprolol (off-label), pro-
pranolol, and timolol, as well as the plant
extract Petasites hybridus (butterbur).
Prescribers should be cautious with the
use of all brands that contain Petasites
as hepatic toxicity from toxic alkaloids
has been described. Refer to the article
‘‘Nutraceutical and Other Modalities for
the Treatment of Headache’’ by Stewart J.
Tepper, MD, FAHS, in this issue of
. A number of drugs not
approved by the US Food and Drug
Administration (FDA) have also been
shown to reduce migraine frequency
by at least 50% as compared with pla-
cebo; these include four beta-blockers
(metoprolol, atenolol, nadolol, and ace-
butolol), one angiotensin II recep-
tor blocker (candesartan), and two
angiotensin-converting enzyme inhibi-
tors (captopril and lisinopril).26
Relatively few studies have assessed
the preventive treatment of chronic

1126 www.ContinuumJournal.com August 2015

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.


migraine. Topiramate has been studied
and shown to be effective for chronic
migraine in placebo-controlled trials.21,22
A randomized trial found that the addi-
tion of propranolol to topiramate was
no better than the addition of placebo
to topiramate in the preventive treatment
of chronic migraine.29 The only FDA-
KEY POINT
approved treatment for chronic migraine h Topiramate has
is onabotulinumtoxinA (Table 12-630Y38), been studied and
which involves injection of 5 units of the shown to be effective
neurotoxin, at 31 head and neck injec- for chronic migraine in
tions every 12 weeks (Table 12-7).10,11 The placebo-controlled trials.
pivotal studies of onabotulinumtoxinA
in chronic migraine are called the Phase 3
Research Evaluating Migraine Prophylaxis

TABLE 12-6 Summary of Randomized Double-blind Controlled Studies of the Efficacy

of Botulinum Toxin Type A in the Treatment of Headache

Headache Type Study Outcome

Migraine
Silberstein et al, Decreased migraine frequency and severity and acute medication use with botulinum
200030 toxin type A (BoNTA) 25 units (U) but not with BoNTA 75 U
Brin et al, 200031 Decreased migraine pain compared to placebo with simultaneous frontal and temporal
BoNTA injections
Evers et al, No difference from placebo in decreased frequency of migraine
200432
Greater decrease in migraine-associated symptoms with BoNTA 16 U
Saper et al, Decreased frequency and severity of migraine in BoNTA and placebo groups with no
200733 between-group differences
Elkind et al, Comparable decreases in migraine frequency in both BoNTA and placebo groups with
200634 no between-group differences
Chronic migraine
Mathew et al, No difference from placebo on primary efficacy end point; change in headache-free
200535 days from baseline at day 180
A significantly higher percentage of BoNTA patients had a Q50% decrease in headache days/
month at day 180 compared to placebo
Dodick et al, Greater decrease in headache frequency after two and three injections compared
200536 to placebo
Silberstein et al, No difference from placebo on primary efficacy end point; change in headache
200537 frequency from baseline at day 180
Greater decrease in headache frequency for BoNTA 225 U and 150 U than placebo
Dodick et al, Two large placebo-controlled, double-blind trials
201023Y25
BoNTA both safe and effective
Chronic tension-type headache
Silberstein et al, No difference from placebo on primary efficacy end point; mean change from baseline
200638 in chronic tension-type headache days
Greater percentage of BoNTA patients than placebo with Q50% reduction in headache
frequency at 90 and 120 days for several doses of BoNTA

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 Medication-Overuse Headache

KEY POINTS
h The only US Food and TABLE 12-7 OnabotulinumtoxinA Dosing for Chronic Migraine,
Drug Administration- by Muscle
approved treatment for
chronic migraine is Total Number of Units (U) (Number of Injection Sites)a
onabotulinumtoxinA.
Head/Neck Area Minimum Dose Maximum Dose
h This author recommends Frontalis 20 U (4 sites) 20 U (4 sites)
the use of acute and
preventive treatment in Corrugator 10 U (2 sites) 10 U (2 sites)
most patients Procerus 5 U (1 site) 5 U (1 site)
with chronic migraine.
Occipitalis 30 U (6 sites) e40 U (5 U per site; e8 sites)
h Most patients need an
acute treatment option Temporalis 40 U (8 sites) e50 U (5 U per site; e10 sites)
to substitute for the Trapezius 30 U (6 sites) e50 U (5 U per site; e10 sites)
overused medication.
Cervical paraspinal 20 U (4 sites) 20 U (4 sites)
Choice of the acute
muscle group
treatment alternative is
based on the class of Total Dose Range: 155 U (31 sites) 195 U (e39 sites)
a
the overused treatment. Each IM injection site = 0.1 mL = 5 U onabotulinumtoxinA.

Therapy (PREEMPT) trials.23Y25 It is also drawal. Table 12-5 summarizes some

effective for patients with chronic mi-
graine and medication overuse.
Acute Medication
This author recommends the use of
acute and preventive treatment in most
patients with chronic migraine. In these
patients, minimizing the use of the over-
used medication or limiting it to 2 or
fewer days per week is desirable. An al-
ternative acute medication may be of-
fered. The optimal approach depends
upon the overused drug and its dose,
headache frequency and severity, the
practices of the clinician, and the pref-
erence of the patient. Broadly speaking,
overused medications may be withdrawn
abruptly or gradually and in an inpatient
or outpatient setting.18,19
For outpatient withdrawal, very often
an alternative acute treatment option is
provided to substitute for the overused
medication on a limited, as needed basis.
Caution is needed for the withdrawal of
barbiturates and opioids. In some cases
a bridge therapy is given on a daily basis
to ease the process of medication with-
1128 www.ContinuumJournal.com
commonly used options. In treating med-
ication overuse, a few principles should
be kept in mind:
1. Begin nonpharmacologic and
behavioral interventions early in
the course of treatment. As
preventive medication becomes
effective, many patients will reduce
their use of acute treatment
because their headaches become
more manageable.
2. Adjust the rate of reduction for the
overused medication based on the
drug, the dose, and the patient’s
response to dose reduction.
3. Most patients need an acute
treatment option to substitute for
the overused medication. Choice of
the acute treatment alternative is
based on the class of the overused
treatment. The most useful classes
of acute treatment options are
triptans (oral or nonoral depending
on the patient), NSAIDs (oral or
nonoral), or dihydroergotamine.
In some patients, dopamine
antagonists may have a role,
although they are usually used as
August 2015

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.


adjunctive medications, especially
in those with nausea.
4. Ensure that the patient does not
overuse the acute treatment
alternative. In this setting, the acute
treatment alternative should be
restricted to use on 2 days per week.
5. A subset of patients require bridge
therapy. Options include long-
acting NSAIDs (eg, naproxen
500 mg 2 times a day), triptans
(eg, naratriptan 2.5 mg 2 times a
day), or steroids (eg, prednisone
60 mg daily for 3 days and then
taper by 10 mg daily to zero). The
choice of bridge therapy is based
both on the overused treatment
and the acute treatment alternative.
For example, if the overused
medication is a butalbital,
acetaminophen, caffeine
combination, then a triptan could
be used as the acute treatment
alternative, and an NSAID or steroid
could be used as the bridge
therapy. If an NSAID is used as the
acute treatment option, then a
triptan could be used as the bridge
therapy. If the overused medication
is a triptan, then an NSAID or
dihydroergotamine could be used
as the acute treatment option or
an NSAID or a steroid could be used
as bridge therapy. One would
not want to give more than one of
aspirin, an NSAID, and steroid to
any patient because of the risk of
gastrointestinal toxicity.
In the case of butalbital-containing
combination tablets or opioids, severe
withdrawal symptoms (eg, tachycardia,
diaphoresis, anxiety, seizure) are possible
after abrupt discontinuation. To avoid
a serious withdrawal syndrome, the
butalbital, acetaminophen, caffeine dose
is gradually lowered. Alternatively, pheno-
barbital can be substituted for butalbital,
acetaminophen, caffeine. A useful and
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KEY POINTS
safe conversion ratio of 30 mg of phe- h A subset of patients
nobarbital for each 100 mg of butalbital require bridge therapy
may be used (eg, 300 mg of pheno- options including
barbital per 20 tablets of butalbital, long-acting NSAIDs (eg,
aspirin, caffeine per day). Phenobarbital naproxen 500 mg
can then be tapered gradually.39 If the 2 times a day), triptans
treatment is an opioid, in the outpatient (eg, naratriptan 2.5 mg
2 times a day), or
setting this author would typically taper
steroids (prednisone
it gradually, using triptans or NSAIDs 60 mg daily for 3 days
acutely and, if need be, triptans, long- and then taper by
acting NSAIDs, or steroids as bridge ther- 10 mg daily to zero).
apy. For patients overusing triptans and The choice of bridge
ergots, this author generally uses NSAIDs therapy is based both on
as bridge therapy. Ergots and triptans the overused
can be safely discontinued abruptly. treatment and the acute
treatment alternative.
h In the case of
CONCLUSION
butalbital-containing
Chronic migraine and medication-
combination tablets or
overuse headache are common in the
opioids, severe
general population and very prevalent withdrawal symptoms
in the clinical practice of neurologists. (eg, tachycardia,
Patients with chronic migraine often diaphoresis, anxiety,
overuse acute headache medications, seizure) are possible after
and in these circumstances, as it is not abrupt discontinuation.
possible to determine whether or in
which direction a causal relationship
exists, both diagnoses are given. The
treatment approach is standardized
and involves the discontinuation of
the overused acute medication, sub-
stitution of selected acute treatments
that are used with limits, and the ini-
tiation of a preventive treatment strat-
egy that includes pharmacologic
prevention, biobehavioral treatments,
and modification of risk factors and
certain lifestyle factors that predict
both progression and relapse.
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