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Medication overuse headache: an overview of

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Abouch V. Krymchantowski , Carla C. Jevoux , Ana G. Krymchantowski ,

Rodrigo Salvador Vivas & Raimundo Silva-Néto

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EXPERT REVIEW OF NEUROTHERAPEUTICS
https://doi.org/10.1080/14737175.2020.1770084

REVIEW

Medication overuse headache: an overview of clinical aspects, mechanisms, and

treatments
Abouch V. Krymchantowskia, Carla C. Jevouxa, Ana G. Krymchantowskia, Rodrigo Salvador Vivasa and Raimundo Silva-Nétob
a
The Headache Center of Rio, Rio de Janeiro, Brazil; bDepartment of Neurology, Universidade Federal do Delta do Parnaíba, Piauí, Brazil

ABSTRACT ARTICLE HISTORY

Introduction: Medication-overuse headache (MOH) is a common debilitating neurological disorder, Received 10 February 2020
with a prevalence of 1% to 7% in general population. It affects more than 60 million people worldwide Accepted 11 May 2020
and provokes substantial burden. Despite that, most practitioners don’t know MOH. This review aims at KEYWORDS
presenting MOH clinical features, pathophysiology insights, and recent knowledge and guidance Medication-overuse
regarding treatments. headache; pathophysiology;
Areas covered: A literature search in the major medical databases including the terms ‘medication withdrawal; treatment
overuse headache,’ ‘chronic daily headache,’ ‘chronic migraine,’ ‘symptomatic medication overuse’ and
others, published between 1990 and 2020, was carried out.
Expert commentary: Primary headache sufferers such as migraineurs and tension-type headache patients
may increase the headache frequency and induce the transition from episodic to chronic forms, as well as
develop MOH, in the presence of medication overuse. There is evidence of structural and functional changes
in some areas of the brain, which may identify those likely to respond or not to treatments. Despite the
geographical differences and lack of consensus regarding approaches, to educate the patients about reducing
medication intake, to withdraw overused medications and to start prophylaxis in some sufferers are crucial
steps. Emerging treatments as monoclonal antibodies to migraine may result in better adherence and
tolerability profiles as well as outcomes.

1. Introduction
Medication-overuse headache (MOH) is a common, debilitat-
ing, and highly prevalent neurological disorder [1–3]. Its pre-
valence ranges from 1% to 7% in the general population and
affects more than 60 million people worldwide, provoking
substantial burden to individuals and to the society [4–6].
Quality of life and work productivity of MOH sufferers are
severely compromised as are their social relationships. The
presence of comorbidities, especially psychiatric and sleep
disturbances is noticeable, resulting in high costs, which over-
pass those of migraine and tension-type headache [4,5].
MOH patients are difficult to treat and the overuse of
symptomatic medications may be cause or consequence of
the frequent headache attacks. Moreover, the mechanisms by
which medication-overuse facilitates migraine or tension-type
headache transformation into a chronic form and how it
results in the so-called medication-overuse headache are still
a matter of debate [7–10]. Only sufferers of primary headaches
such as migraine and tension-type headache seem to develop
MOH in the presence of medication overuse [8,9,11–13].
Criteria that define medication overuse, considering the
different types of medications, are presented in the current
version of the International Headache Society Classification
(ICHD-3) [7]. According to it, the intake of simple analgesics
or non-steroidal anti-inflammatories on 15 or more days per
month or the intake of combination of analgesics and caffeine,
triptans, and/or ergotamine derivatives on 10 or more days
per month constitute overuse [7]. The use of opioids, barbitu-
rates, and benzodiazepines is even worse regarding induction
of MOH and two or more days per week may lead to trans-
formation [7]. Therefore, different classes of acute headache
medications seem to lead to MOH with different intensities
and duration of overuse [14,15].
Treatments for MOH vary with patients’ subpopulations,
cultures, and countries [16–21]. In Scandinavian countries, for
instance, complete detoxification, strict orientation, and close
follow up carried out by the competent staff of Danish
Headache Center for example, may be enough to provide
decreasing headache frequency, reversal to the episodic pat-
tern of headache attacks in less than 15 days per month and
treatment adherence [6,16,19].
On the other hand, different treatment strategies seem to
be necessary in countries like USA and Brazil, where the
frequent use of opioids, barbiturates or benzodiazepines, or
the high prevalence of psychiatric comorbidities, usually
require bridge transition therapies like dihydroergotamine or
prednisone during the initial days of detoxification [18,20–22].
In addition, the initiation of preventive treatments using either
monotherapy or rational combination of drugs represents the
most effective and practiced way of achieving both headache

CONTACT Abouch V. Krymchantowski abouchkrym@uol.com.br The Headache Center of Rio, Rua Siqueira Campos 43/1002, Copacabana, Rio De Janeiro,
RJ 22031-071, Brazil
© 2020 Informa UK Limited, trading as Taylor & Francis Group
2 A. V. KRYMCHANTOWSKI ET AL.
Article highlights
● MOH is highly prevalent in neurology practice and imposes a heavy
burden to sufferers.
● Patients and general physicians are not aware of basic factors about
MOH presentation, pathophysiology and treatment, therefore impair-
ing its recognition.
● Treatment varies between countries, cultures, societies, and health
professionals, but withdrawal of overused medications seems to be
the most effective initial approach.
● Choosing and initiating preventive treatment with drugs, the right
time to do it or the superiority of combining medications rather than
using monotherapy, still need more evidence.
● Emerging therapies such as monoclonal antibodies may represent
better options in comparison to what is currently available.
● Non-pharmacological therapies may also be effective pending further
controlled studies.
improvement and treatment adherence [18,20–22]. Regardless
of the chosen treatment, withdrawal of overused symptomatic
medications is the core of the treatment despite recent evi-
dence of headache improvement with the use of topiramate,
onabotulinum toxin A and monoclonal antibodies anti-CGRP
in migraineurs with MOH even without detoxification [23,24].
However, despite the immense burden, treatment difficulties
and considerable relapse rates, MOH is a preventable and
treatable pathological condition [23].
Because of its severe impact, evolutive characteristics, and
lack of consensus regarding treatments and approaches, we
aimed at reviewing pertinent literature and offer clinicians
crucial points to identify and treat, perhaps more efficiently,
the MOH sufferers.
2. Classification and clinical features
Medication-overuse headache is classified in the group 8 of the
International Classification of Headache Disorders, 3rd edition.
(ICHD-3), which is nominated headache attributed to a substance
or its withdrawal [7]. The specific sub-item on medication-
overuse headache is presented with the number 8.2 (Table 1).
Clinically, the MOH patients have migraine or tension-type
headache as their primary headache, usually episodic, that
started in the second or third decades. In some subpopulations
of patients, at around 30–40 years of age (33.8 ± 12.3 for female
patients; 37.8 ± 10.4 for male patients) [25], the headaches
became more frequent with the time and lose typical features
of migraine such as photophobia, osmophobia, phonophobia,
and the gastrointestinal symptoms of nausea and vomiting
[25,26]. Other patients start with episodic migraine with aura,
which evolves into attacks of migraine without aura and daily
headache occur subsequently [25,26].
Other migraine characteristics such as menstrual aggrava-
tion, identifiable migraine triggers, and unilateral headache
may be present [25–29]. Most patients may present a clear
family history of migraine and keep intermittent full-blown
migraine attacks with variable frequency [25–29].
Moreover, MOH sufferers evolving from episodic migraine
frequently reveal psychological and/or sleep disturbances,
Table 1. Group 8 of the ICHD-3 [7].
8 Headache attributed to a substance or its withdrawal
8.1 Headache attributed to use of or exposure to a substance
8.1.1 Nitric oxide (NO) donor-induced headache
8.1.1.1 Immediate NO donor-induced headache
8.1.1.2 Delayed NO donor-induced headache
8.1.2 Phosphodiesterase (PDE) inhibitor-induced headache
8.1.3 Carbonmonoxide (CO)-induced headache
8.1.4 Alcohol-induced headache
8.1.4.1 Immediate alcohol-induced headache
8.1.4.2 Delayed alcohol-induced headache
8.1.5 Cocaine-induced headache
8.1.6 Histamine-induced headache
8.1.6.1 Immediate histamine-induced headache
8.1.6.2 Delayed histamine-induced headache
8.1.7 Calcitonin gene-related peptide (CGRP)-induced headache
8.1.7.1 Immediate CGRP-induced headache
8.1.7.2 Delayed histamine-induced headache
8.1.8 Headache attributed to exogenous acute pressor agent
8.1.9 Headache attributed to occasional use of non-headache medication
8.1.10 Headache attributed to occasional use of non-headache
medication
8.1.11 Headache attributed to use of or exposure to other substance
8.2 Medication-overuse headache (MOH)
8.2.1 Ergotamine-overuse headache
8.2.2 Triptan-overuse headache
8.2.3 Non-opioid analgesic-overuse headache
8.2.3.1 Paracetamol (acetaminophen)-overuse headache
8.2.3.2 Non-steroidal anti-inflammatory drug (NSAID)-overuse
headache
8.2.3.2.1 Acetyl salicylic acid-overuse headache
8.2.3.3 Other non-opioid analgesic-overuse headache
8.2.4 Opioid-overuse headache
8.2.5 Combination-analgesic-overuse headache
8.2.6 Medication-overuse headache attributed to multiple drug classes
not individually overused
8.2.7 Medication-overuse headache attributed to unspecified or
unverified overuse of multiple drug classes
8.2.8 Medication-overuse headache attributed to other medication
8.3 Headache attributed to substance withdrawal
8.3.1 Caffeine-withdrawal headache
8.3.2 Opioid-withdrawal headache
8.3.3 Estrogen-withdrawal headache
8.3.4 Headache attributed to withdrawal from chronic use of other
substance
which contribute to transformation or perpetuation into the
chronic migraine presentation [25,26,30].
The overuse of symptomatic medications becomes more
consistent with the time and is anticipated with increased
refractoriness and subsequent escalation of the number of
headache days [30]. This clinical behavior was demonstrated
elegantly by Bigal et al., who reported in the American
Migraine Prevalence and Prevention study (AMPP) that drug
combinations with barbiturates (as butalbital) predict the
1-year transformation of episodic migraine to MOH if used 5
or more days per month, opioids if taken 8 or more days per
month, and triptans if taken 10 or more days per month.
However, nonsteroidal anti-inflammatory drugs (NSAIDs) if
used 5 or fewer days per month revealed a protective effect
against MOH but could result in medication-overuse headache
if taken 10 or more days per month [31].
The triptans are frequently overused nowadays and may be
considered the most common inducers of MOH in specific
countries such as Denmark, Italy, and Lithuania [32].
Interestingly, triptan overuse appears to cause MOH faster
even if used in lower doses than other drugs [33].
 EXPERT REVIEW OF NEUROTHERAPEUTICS 3

3. Methods Table 3. Distribution of frequencies and percentages related to the clinical

characteristics of chronic migraineurs [25].
Based on a literature search in the major medical databases Women
(LiLacs, SciELO, Bireme, Scopus, EBSCO, and PubMed), using Men (n = 54) (n = 217)
the terms ‘medication-overuse headache,’ ‘medication overuse Clinical characteristics Frequency % Frequency % p value
headache,’ ‘headache symptomatic medication overuse,’ Headache location 0.110
‘chronic daily headache,’ ‘transformed migraine and medication Bilateral frontotemporal 28 51.8 118 54.4
Diffuse 11 20.4 62 28.6
overuse,’ ‘tension-type headache and medication overuse’ and Hemicranium right or left 7 13.0 12 5.5
‘chronic migraine and medication overuse,’ we conducted an Unilateral frontotemporal 8 14.8 25 11.5
integrative review of articles published between 1990 and 2019. right or left
Headache intensity 0.180
In all articles, we seek recent knowledge on the pathophy- Mild 20 37.0 55 25.3
siology and most effective treatments for patients with MOH. Moderate 22 40.8 115 53.0
Diagnostic criteria for MOH were established according to ICHD- Moderate to severe/severe 12 22.2 47 21.7
Quality of headache 0.260
3 and ICHD-3 (beta) (before 2013, there was no consensus on Pressure/tightening 32 59.3 158 72.8
nominating chronic migraine or tension-type headache and Pulsatile/throbbing 17 31.5 44 20.3
medication-overuse headache, but studies including patients Pressure/tightening 3 5.5 8 3.7
+pulsatile
with transformation to chronic daily or near-daily headaches Burning 2 3.7 7 3.2
and medication overuse were also evaluated) [7,34]. Progressive onset? (for non- 0.500
Data were analyzed based on clinical features, therapeutic continuous headache)
Yes 41 75.9 155 71.4
experience, and clinical outcomes. This data was presented as No 13 24.1 62 28.6
arithmetic mean with the standard deviation (SD) or as per- Headache duration 0.310
centages. The chi-square test with Yates correction was used Continuous 14 25.9 47 21.7
1–4 hours 10 18.5 21 9.7
for the difference of means of unpaired samples, with 4–6 hours 1 1.8 16 7.4
a significance level of 0.05. 6–8 hours 11 20.4 67 30.9
All collected data were organized in database. The Statistical 8–12 hours 15 27.8 43 19.8
>12 hours 3 5.6 9 4.1
Package for Social Sciences (SPSS™) version 17.0 was used for Undefined - - 14 6.4
statistical analysis.

4. Results Table 4. Distribution of frequencies and percentages of the relationship

between transformed/chronic migraine patients (TM) and sleep [25].
In a thorough study of 300 consecutive patients from a tertiary Women
center with headache in ≥15 days/month, 271 had migraine as Men (n = 54) (n = 217)
their primary headache [25]. The details on the headache Discrimination Frequency % Frequency % p value
characteristics and evolution with the time are presented in Headache upon waking in the 0.640
morning?
Table 2. Differences in clinical characteristics were observed Yes 11 20.4 39 18.0
regarding gender, as shown in Tables 3–5. No 43 79.6 178 82.0
Indeed, the pain location in MOH varies and frequently differs Wakes with headache during 0.001
the night?
from the primary headache location when headache was episo- Yes 8 14.8 151 69.5
dic [30]. Patients tend to describe different types of headaches, No 46 85.2 66 30.5

Table 2. Distribution of frequencies and percentages related to the temporal

characteristics of migraine patient’s evolution [25]. such as diffuse, in the forehead, temples, back of the head or
Men (n = 54) Women (n = 217) occipital, unilateral, or bilateral, leading the patients, wrongly, to
Discrimination Frequency % Frequency % p value
assume that they have different types of headaches. Neck pain is
Duration of EM (years) 0.110
reported by the vast majority of MOH patients, also leading to an
Up to 3 10 18.5 39 18.0 incorrect diagnosis of cervicogenic headache or to inefficient or
4–8 24 44.4 42 19.4 unnecessary and costly neck interventions [30].
8–12 - - 18 8.3
12–16 4 7.4 49 22.6
Patients who overuse ergotamine and simple analgesics
16–20 4 7.4 12 5.5 may more likely to present the daily headache with tension-
20–30 6 11.1 32 14.7 type features, while triptan-induced MOH may provoke daily
30–40 1 1.9 11 5.0
> 40 5 9.3 14 6.5
headache with more migrainous features [15]. MOH caused by
Duration of CDH (years) 0.008 the combined overuse of triptans and analgesics typically
0.5–1 year 23 42.6 113 52.0 manifests progressive higher headache frequency and inten-
1–3 17 31.5 27 12.5
3–6 10 18.5 53 24.5
sity as well as more additional symptoms than the overuse of
6–10 4 7.4 6 2.7 triptans alone [35]. The initiation and progression of the head-
>10 - - 18 8.3 ache attack among those patients with non-continuous pain
Noticed frequency increase? 0.030
Yes 45 83.3 149 68.7
and the duration of pain are also shown in Table 3.
No 9 16.7 68 31.3 Headache and sleep may be related. It could be present
Note: EM – episodic migraine; CDH – chronic daily headache. upon waking up in the morning (18% female patients and
4 A. V. KRYMCHANTOWSKI ET AL.

Table 5. Distribution of frequencies and percentages related to the headache must be emphasized that 186 female patients (89.8%) and
associated symptoms of the transformed/chronic migraine patients (TM) [25]. 39 male patients (88.6%) reported clearly more than one
Men (n = 54) Women (n = 217) trigger factor [25].
Symptoms Frequency % Frequency % p value The excessive consumption or overuse of symptomatic
Nausea 0.550 medications (SM), according to the ICHD-3 [7], was observed
Yes 31 57.4 134 61.7
No 23 42.6 83 38.3 in nearly 90% of the patients with migraine, which evolved
Vomiting 0.590 into daily or near-daily headache (182 female patients (83.8%)
Yes 6 11.1 19 8.7 and in 47 male patients (87%)) [25].
No 48 88.9 198 91.3 0.050
Photophobia It is worth noticing that non-migraineurs who use frequent
Yes 16 29.6 96 44.2 and regular opioids or barbiturates for other types of chronic
No 38 70.4 121 55.8 pain may develop drug dependency and even MOH, but not
Phonophobia 0.870
Yes 18 33.0 70 32.3 as frequently and clearly as migraineurs [11,30]. This is not
No 36 67.0 147 67.7 fully understood yet, but it was demonstrated in patients
Osmophobia 0.700 using daily analgesics (62.5% used opioids) for rheumatologic
Yes 11 20.4 49 22.6
No 43 79.6 168 77.4 conditions, who developed MOH at a significantly higher rate
when they had episodic migraine in comparison to those
without headache [11].
20.4% male patients) or interrupting sleep during the night Refractoriness to preventive and even acute medications in
(69.5% female and 14.8% male patients) [25] (Table 4). the setting of MOH is frequently seen [36–39]. The patients
Early morning presentation of headache, secondary to noc- commonly present a huge list of medications that were tried
turnal withdrawal or to a non-restorative sleep also related without success, although many may have been used in
to drug withdrawal, may also manifest in MOH sufferers incorrect doses or for insufficient time [20,28,29,36,39].
[25,36]. One could argue on whether the increased caffeine Additionally, the preventive treatments may have been experi-
consumption (combination analgesics usually contain caf- enced with patients not withdrawing from offending medica-
feine) may represent a further factor increasing the head- tions, since interrupting the pattern of overuse promotes
ache itself or the sleep disturbances [25,36] (Table 4). better outcomes regarding prophylaxis effectiveness
Associated symptoms may diminish or disappear in migrai- [20,26,29,36,39].
neurs who develop MOH, especially if the headache becomes As a summary, for clinicians to suspect on MOH even when
daily or near-daily [8,20,25,30] (Table 5). In addition, full-blown it is not referred, the existence of a pressure-type or dull
intermittent migraine attacks were observed in most of the diffuse headache, with intermittent typical attacks of migraine,
patients [25] (Table 6). presenting progressive higher frequency, in patients with pre-
Despite the higher frequency of headache in MOH vious episodic migraine and a family history of migraine,
patients, trigger factors of the intermittent typical migraine which awaken the sufferer during the night or in the first
attacks were still reported as menstruation (61.8%), inges- morning hours, not responding to preventive agents and
tion of alcohol (11.1% female and 15.9% male patients), reporting partial response to acute medications, should raise
ingestion of chocolate (13% and 6.8%), fatigue (31.4% and suspicion on this diagnosis and lead to a more thorough
22.7%), sleeping longer than usual (18.4% and 13.6%), sleep evaluation [23,25,26].
deprivation (46.4% and 52.3%), fasting or skipping a meal
(48.3% and 41%) and stressful events (79.2% and 73%). It
5. Pathophysiology insights
Recent brain imaging studies have shown MOH as a functional
Table 6. Distribution of frequency and percentages related to the features of and structural neurological disease [10,40,41]. The metabolism
intermittent attacks with typical migraine features in patients with TM [25]. is altered in some specific areas of the brain in addition to
Women decreasing gray matter volumes in specific brain nuclei [40].
Men (n = 44) (n = 207)
The total gray matter volume of a MOH patient’s brain is
Discrimination clinical
significantly lower than that of a healthy control’s brain.
presentation Frequency % Frequency % p value
Additionally, areas associated with migraine pathophysiology,
Similar to the daily headache 13 29.6 72 34.7 0.700
but more severe and with pain processing and within regions implicated in the addiction
exacerbation of associated process seem to be those with greater gray matter volume
features
alterations [10,41].
Different from the daily 28 63.6 48 23.2 0.001
headache becoming MOH patients have less gray matter volume in the left middle
pulsatile and more severe occipital gyrus and in the orbital frontal cortex in comparison
Different from the daily 3 6.8 36 17.4 0.008
with chronic migraineurs without medication overuse [42]. The
headache becoming
unilateral and with anterior cingulate cortex, the insula, the precuneus, left amyg-
associated symptoms dala, and left hippocampus have also less gray matter volume in
Different from the daily - - 21 10.2 -
MOH patients [40]. On the other hand, areas of pain modulation
headache becoming
unilateral pulsatile and with as the periaqueductal gray matter, thalamus and ventral striatum
associated symptoms as well as the left temporal pole reveal increased volumes. The
Undefined - - 30 14.5 -
meaning of these differences is still controversial, but MOH is

indeed associated with dysfunction of modulating and pain
processing regions additionally to nuclei involved in rewarding
circuits, which is not known yet whether it possesses a causal
relationship with the development of MOH [10,42].
Regarding the brain function in MOH subjects, there is less
pain-induced activation in the inferior parietal lobule, supra-
marginal, and postcentral gyrus, which are nuclei of the pain
system involving projections from the lateral thalamus to the
cortex [43]. Moreover, there is altered coupling between sev-
eral brain areas in MOH patients. The coupling inhibition of
the axis Orbital frontal cortex (OFC) – trigeminal pathways –
cortical functioning is probably due to the regular and con-
stant intake of analgesics or pain killers, which may impair the
working capacity of integrating central networks responsible
for computing sensory modalities [44,45]. Other studies eval-
uating functional connectivity revealed abnormalities between
pain processing nuclei as well as temporal and hippocampal
areas with the precuneus, which is involved in awareness, self-
reflection and episodic memory in MOH patients [46].
Taken together, medication-overuse headache is indeed asso-
ciated with function and structural changes in areas related to
pain modulation, pain processing (sensory-discriminative), cog-
nitive and affective components of pain (hippocampus and ante-
rior insula), addiction (orbitofrontal cortex) and episodic memory
as well as awareness and self-reflection (precuneus) [10]. These
changes in brain morphology and function may overlap with
abnormalities encountered in the pathophysiology of addiction,
involving, in both processes, mesocorticolimbic pathways of the
dopaminergic system, which remain abnormal following discon-
tinuation of overused medications [10,47,48]. It is possible that
such abnormalities predispose the patients to develop MOH.
Contrarily, the altered brain regions involved in pain processing
are likely to normalize following discontinuation of overused
medications and successful treatment of MOH, therefore sug-
gesting a secondary origin related to the overuse of symptomatic
medications and associated headaches [10,48,49].
Regardless of whether these atypical function and structural
changes normalize after withdrawal of overused medications
reflecting its consequence rather than a causal mechanism or
do remain after its interruption, suggesting a predisposition for
developing MOH in some subjects, there is no question on the
need and importance of medication-overuse stop [50].
6. Treatment
Although MOH has been known for half a century and
imposes heavy and costly burden, its treatment has been
a matter of disagreement among specialists worldwide
[18,24,51]. Despite controversies and particulars of different
regions and ways of approaching these patients, it seems to
be a consensus the need to educate and inform the sufferers
about reducing or interrupting medication intake [52]. In fact,
it has been documented that even after simple advice, many
MOH patients are able to revert to a pattern no longer ful-
filling the criteria for medication overuse [50].
Interestingly, most studies suggesting advice alone as use-
ful for improving MOH and reversing to episodic medication
intake comes from Scandinavian countries and Northern
EXPERT REVIEW OF NEUROTHERAPEUTICS 5
European countries where the socialized medicine with its
efficient supporting roles of headache nurses and paramedical
professionals as well as the lower use of opioids, barbiturates,
and benzodiazepines may help adherence and effectiveness of
educational programs for the patients [53]. As for Brazilian and
perhaps for American patients, where overuse of more aggres-
sive medications, greater prevalence of psychiatric comorbid-
ities other than depression/anxiety and absence of
a competent structure of universal care, bridging withdrawal
phases with drug options and initiating preventative treat-
ments, sometimes with a rational combination of drugs, may
be determinant for success and adherence [18,21,54].
Real-world comparisons regarding costs and relative effect
size between these different realities and approaches could be
useful for guiding clinicians from various geographical regions
on the most effective ways of treating their patients, but
studies using placebo as a comparator and even non-
pharmacological therapies can’t be carried out with specific
populations of patients [17,21,55,56].
With this regard, non-pharmacologic treatments have been
advocated as well, but the likelihood that such approaches
alone will be effective is restricted. However, the use of nurses
trained in headache, the availability of an electronic dairy
linking the patient to a health professional and even short
periods of psychological support after withdrawal may result
in reduction of medication overuse and less likelihood of
relapsing [55]. Psychological treatments as mindfulness are
also suggested as useful tools for MOH patients. In a study
from an Italian group, the single use of a mindfulness-based
approach was similar, in efficacy, to a conventional pharma-
cological approach suggesting that both treatments are
equally useful [17].
Despite that, withdrawal of overused medications is the
core of the treatment. Although the best way of withdrawing
has been a matter of controversy, there is still doubt on
whether total and sudden suspension of overused medica-
tions is possible to be performed with all kinds of patients
[19,50,57–60]. In addition, it is not clear yet whether postpon-
ing prophylaxis is superior than starting it immediately after
withdrawal [19,50,57–60].
Studies comparing initial use of prophylaxis versus post-
poning it provided conflicting results. Hagen et al. demon-
strated better efficacy in starting preventive treatments right
after interrupting the overuse of symptomatic medications,
but the studies performed by Munksgaard and Rossi’s groups
totalizing 216 patients showed similar number of dropouts
and headache frequency reduction among those who
received prophylaxis initially or after 2 months of overused
medications suspension [50,53,61].
Different approaches carried out in different regions
demonstrated efficacy as well. In Brazilian patients from
a tertiary clinic for example, 149 consecutive sufferers with
a baseline headache frequency of 24.8 ± 5.9 days/month, who
used symptomatic medications in 22.6 ± 6.4 days/month, were
treated with sudden withdraw of overused medications, use of
prednisone during the initial 5–7 days (67.7%) and starting
prevention composed by different drugs or combination of
drugs from the seventh day onwards. After 4 and 8 months,
6 A. V. KRYMCHANTOWSKI ET AL.
headache frequency decreased to 7.6–8.3 days/month (per
protocol) and 11.2–11.4 (intention-to-treat) [18].
Regarding the choice of preventive pharmacological
agents, there is no robust evidence to suggest specific medi-
cations. Few studies evaluated specifically MOH sufferers
despite the coexistence of chronic migraine or chronic daily
headache. Sodium divalproate (SD) was evaluated for chronic
migraineurs with medication overuse in the dose of 800 mg/
day compared to placebo along with detoxification [62]. The
study had a titration phase of 5 days, but lasted 24 weeks,
being the first 12 weeks with the use of divalproate or placebo
and 12 subsequent weeks without medication. The patients
using SD had a significantly larger reduction in headache
frequency compared to the placebo group during the treat-
ment phase (8.1 headache days/month versus 4.6), but at
week 24, no differences were observed between groups,
demonstrating not only the effectiveness of SD but the
absence of a carry-over effect [62].
Topiramate was also studied in MOH patients. In one trial with
59 subjects presenting chronic migraine, Diener et al. suggested
that withdrawing overused medications may not be necessary
when using topiramate [63]. The authors obtained a reduction of
3.5 headache days/month versus an increase of 0.8 headache
days/month in the placebo group. Paresthesia, taste distur-
bances, fatigue, and memory alterations were among adverse
events experienced more frequently in the topiramate group of
patients in comparison to placebo patients and resulted in
higher dropout rates [63].
In another study, using topiramate (TPM) 50–100 mg/day in
a titration period of 4 weeks followed by a treatment phase of
8 more weeks and changing the acute treatment of attacks to
triptans resulted in a significant decrease of headache fre-
quency compared to a placebo group who did not change
the acute medication pattern of use and used placebo instead
of topiramate [64]. Fifty patients were randomized either to
TPM (30 patients) or placebo (20 subjects) in addition to
evaluate the administration of a triptan or placebo for the
acute migraine episodes.
Significant reductions in headache frequency and in the
amount of acute medications taken were observed in the
TPM group. As expected, the patients who took triptans per-
formed significantly better than those who used placebo for
the treatment of the attacks [64].
The experience of the present review’s authors regarding
TPM for chronic migraine and MOH do not confirm the obser-
vations of these studies. Our personal experience is that TPM
is useful, but withdrawal of overused medications is crucial
and a pre-requisite for improvement [18,65].
Pregabalin was studied for chronic daily headache with med-
ication overuse in comparison to TPM. Forty-six patients used
pregabalin 150 mg/day versus 42 who used TPM 100 mg/day
after a titration period of 4 weeks. A significant and similar
reduction in headache frequency, symptomatic medication con-
sumption, and disability scores was observed with both medica-
tions. The tolerability of both drugs was equivalent as well [66].
The cannabinoid nabilone was evaluated for intractable MOH
patients in a randomized, double-blind, active-controlled, cross-
over study in Italy with 30 patients. The subjects received 0.5 mg/
day of oral nabilone for 8 weeks followed by 8 more weeks in
which 400 mg ibuprofen was given daily in a blinded sequence.
Between the two active drug periods, there was a wash-out
phase of 1 week [67]. The synthetic cannabinoid CB1-receptor
agonist nabilone was significantly superior than ibuprofen after
20 weeks of follow up in reducing headache severity, consump-
tion of acute medications, and in improving quality of life (QoL)
indicators such as Short-Form (SF)-36. Despite the conclusion
that nabilone is efficacious for the MOH treatment, the knowl-
edge about its long-term efficacy and safety is warranted accord-
ing to the authors of the study [67].
Despite the efficacy figures or the potential usefulness of
these two drugs in MOH, addiction potential has been sug-
gested, which must be considered when possibly choosing
pregabalin or nabilone [68,69].
Onabotulinumtoxin A (OBTA) has been suggested for
chronic migraine since the beginning of this decade, but for
MOH patients it has demonstrating diverging and conflicting
results with a clear tendency for lack of efficacy [70–72]. In
a secondary subgroup analysis of the PREEMPT study in sub-
jects with medication-overuse headache who did not detox-
ified and received two cycles of 155–195 U injections, the
headache frequency reduction was similar for OBTA and pla-
cebo patients at week 24 after treatment [70]. Additionally,
another study using 100 U compared to placebo in MOH
sufferers treated with an inpatient program of detoxification
resulted in similar reduction in headache frequency at week 12
(12.2 versus 10.3 days/month) [71].
Moreover, in a recent study done in the Netherlands with 179
randomized chronic migraineurs with overuse of symptomatic
medications, 90 subjects received 155 U of OBTA and 89 subjects
received saline plus 17.5 U (to reduce unblinding) as placebo, in
31 injection points after withdrawing acutely in an outpatient
fashion [72]. It was observed that Onabotulinumtoxin A was not
superior to placebo in reducing monthly headache days (differ-
ence -6.4%; -26.9% versus -20.5%; confidence interval 95%;
p = 0.15), nor absolute changes in migraine days at 12 weeks
(difference 0.8; -6.2 versus -7.0; confidence interval 95%;
p = 0.38) [72].
Other secondary endpoints, as parameters of quality of life
and disability, did also not differ. The withdrawal phase was
well tolerated and blinding with 17.5 U in the forehead was
successful. The authors concluded that in patients with
chronic migraine and medication overuse, OBTA does not
provide any additional benefit over acute withdrawal alone
and the acute withdrawal should be always tried first before
initiating more expensive and not efficient treatments with
OBTA [72].
Based on the data from recent literature and especially
considering the previous experience of many patients attend-
ing our center, we don’t use and recommend OBTA for the
treatment of medication-overuse patients regardless of their
primary headache type.
The new therapies anti-CGRP (calcitonin gene-related pep-
tide) have also been suggested for chronic migraine with MOH.
Erenumab, the only monoclonal antibody blocking the CGRP
receptor, which has been demonstrated as an effective and

safe migraine therapy, was evaluated in a sub-group analysis for
chronic migraineurs with overuse of acute medications [73].
In this placebo-controlled, double-blind study of 667 adults
with chronic migraine, there was a randomization of 3:2:2 to
placebo or erenumab 70 or 140 mg. The subjects were grouped
by medication overuse (MO) status as well as by region. Those
with MO at baseline had their data used to assess differences
and variations in reducing monthly migraine days, in proportion
of subjects achieving ≥50% reduction in monthly migraine days
and in days in which acute migraine-specific medications were
consumed [73].
Of the initial 667 patients randomized, 41% (n = 274) met
medication-overuse criteria and didn’t withdraw. In this sub-
group, the use of erenumab 70 or 140 mg lead to greater
reductions than in the placebo group at month 3, regarding
monthly migraine days (mean −6.6 [−8.0 to−5.3] and −6.6
[−8.0 to −5.3] versus −3.5 [−4.6 to −2.4] [95% confidence
interval]). The acute migraine-specific medication treatment
days were significantly reduced when compared to the pla-
cebo group (−5.4 [−6.5 to −4.4] and −4.9 [−6.0 to −3.8] versus
−2.1 [−3.0 to −1.2]) [73].
The endpoint ≥50% reductions in monthly migraine days
were achieved, respectively, by 18%, 36% (odds ratio [95%
confidence interval] 2.67 [1.36–5.22]) and 35% (odds ratio
2.51[1.28–4.94]) of the patients treated with placebo, erenu-
mab 70 mg and erenumab 140 mg. It was therefore demon-
strated that erenumab resulted in better outcome measures of
impact, disability, and health-related quality of life, with posi-
tive treatment effects similar among medication overuse and
non-medication overuse subgroups of patients [73].
Galcanezumab was also studied for episodic and chronic
migraineurs and medication-overuse headache in post hoc analy-
sis of the phase 3 double-blind, randomized, placebo-controlled
studies EVOLVE-1, EVOLVE-2, and REGAIN [74]. In the EVOLVE trials,
the patients had 4 to 14 monthly migraine headache days [MHDs];
in the REGAIN study, patients had ≥15 monthly MHDs for
>3 months. The sufferers in each study were randomized 2:1:1 to
monthly subcutaneous injections of placebo or galcanezumab
120 or 240 mg/month for 3–6 months. The data on medication
overuse were gathered in electronic diaries using criteria adapted
from the ICHD-3 [7]. The proportions of patients with medication
overuse after randomization were estimated, respectively, in
19.3% and 19.2% for EVOLVE studies (-1 and -2), and 63.9% for
REGAIN [74].
The improvement was statistically significant (p < 0.001) for
reductions in monthly migraine headache days in MOH sufferers
across EVOLVE-1, EVOLVE-2, and REGAIN trials (REGAIN study:
galcanezumab 120 mg = -4.78; galcanezumab 240 mg = -4.51
versus placebo = -2.25; EVOLVE-1 and -2 studies: galcanezumab
120 mg = -6.26; galcanezumab 240 mg = -5.77 versus placebo = -
2.71). It is noteworthy that patients with MOH at baseline
revealed a significantly lower use of these treatments for galca-
nezumab in 120 mg and 240 mg doses in comparison to placebo
across the three studies (p < 0.001) (for REGAIN trial, galcanezu-
mab 120 mg = 24.3%; 240 mg = 23.1% and placebo = 40.6%; for
EVOLVE-1 and -2 trials, galcanezumab 120 mg = 6.2%,
240 mg = 7.9% and placebo = 15.9%). As with erenumab, the
findings with galcanezumab were similar to those observed with
EXPERT REVIEW OF NEUROTHERAPEUTICS 7
subjects without MOH at baseline, as well as in the overall intent-
to-treat patients of the three studies [74].
Fremanezumab was perhaps the best studied monoclonal
antibody for chronic migraine patients. Trials with similar design
were performed for phase 2 and phase 3 [75,76]. Each study
tested two dose levels in comparison to placebo during
a period of 4 months divided as follows: 1 month as prospective
run-in phase followed by the phases of randomization and treat-
ment lasting three more months. A total amount of 1,393 sub-
jects with the diagnosis of chronic migraine were included, with
928 patients having received fremanezumab. Among those
receiving the active treatment, 376 patients received 675 mg in
the quarterly dosing; 467 received 675 mg initially followed by
225 mg monthly and 86 patients received 900 mg monthly
(which was tested in phase 2 but not in phase 3). The same
endpoints were collected in each trial.
Patients could be on preventive medication, which also was
a unique aspect of fremanezumab development, thanks to the
leadership and visionary work of Marcelo Bigal. In both stu-
dies, patients had around 21 headache days per month, with
nearly 65% of these days with moderate or severe attacks. In
addition, there was the use of symptomatic medications in an
average of 13 (Phase 3) to 15 (Phase 2) days per month [75,76].
In the Phase 2 trial, two dose regimens were used:
a loading dose of 675 mg followed by monthly doses of
225 mg and monthly doses of 900 mg [75]. The primary
outcome evaluated the mean change from baseline in the
number of monthly headache hours of any severity during
the 28-day post-treatment period ending with week 12. The
secondary endpoint was the decrease in the monthly aver-
age number of headache days of at least moderate severity
for the 28-day post-treatment period ending with week 12.
A crucial point was that participants could be taking up to
two different types of preventive medications without limit-
ing the number of studied patients taking these pharmaco-
logical agents. Efficacy was achieved in the first 4 weeks of
therapy, and incremental benefits were seen with the con-
tinuation of therapy [75].
The group who received placebo revealed a monthly
decrease of 3.8 days with headache of moderate or severe
intensity, which represents -11.5 days for the length of the
trial. The patients who received the doses 675 mg/225 mg and
225 mg had -16.8 days for the study or a monthly decrease
achieving 5.58 days (45.2% superior to placebo). Those who
received three monthly doses of 900 mg presented -5.9 days
of moderate or severe headache, which represents -17.7 days
for the duration of the trial (54.1% superior to placebo) [75].
In the Phase 3 study, we also observed the testing of two
distinct subcutaneous dose regimens: 675 mg/placebo/pla-
cebo (supporting a quarterly dose regimen) and 675/225/
225 mg (supporting a monthly dose regimen after a loading
dose) [76]. The primary endpoint was a decrease in the
monthly average number of headache days of at least mod-
erate severity during the 12-week period after the first dose in
comparison to the baseline. In this study, the evaluation was
not performed only in the last month of the trial. Here, parti-
cipants could be on one (but not on two) simultaneous pre-
ventive medications [76].
8 A. V. KRYMCHANTOWSKI ET AL.
A significant impact on the number of headache days was
seen with a reduction of −14.8 for the monthly dose (68.2%
superior to placebo), −14.1 for the quarterly dose (60.1%
superior to placebo) and −8.8 days for placebo.
The monthly days with the use of any acute headache
medication also decreased significantly from baseline to
week 12, for the quarterly dose (-3.7; p < 0.001 versus placebo)
and for the monthly dose (-4.2; p < 0.0001 versus placebo) in
comparison to placebo (-1.9).
Collectively, all three mAbs reduced significantly compared
to placebo, the monthly migraine days and the days in which
the patients used symptomatic medications among the suf-
ferers with chronic migraine who were overusing drugs for the
acute treatment, across the studies carried out with erenumab,
galcanezumab, and fremanezumab. Roughly, 41% of 667
patients studied for erenumab (70 mg, 140 mg or placebo),
63.9% of 1113 patients studied for galcanezumab (120 mg,
240 mg or placebo) and 50% of 1130 patients studied for
fremanezumab (225 mg, 675 mg or placebo) were overusers
of symptomatic headache medications.
7. Conclusions
We conclude that regular or frequent use of headache symp-
tomatic medications can increase the frequency of headache
and induce the transition from episodic to chronic headache
or medication-overuse headache. It happens in patients with
primary headaches as migraine and tension-type headache. In
addition, there may be subgroups of migraineurs who are
more prone to this evolution and who will not respond to
the treatment. Although no consensus exists regarding the
best treatment options, to reduce or discontinue the use of
offending medications may be crucial for achieving headache
frequency reduction and treatment adherence. Educating
health professionals and patients about MOH is an important
tool to improve outcomes. The possibility that emerging
therapies and nonpharmacological treatments will render bet-
ter results is still under scrutiny and will probably be presented
soon, despite the few currently available studies with non-
pharmacological treatments.
8. Expert opinion
Medication-overuse headache is highly prevalent in neurology
practice. Those who suffer live with a heavy burden. However,
MOH is not always easily identified and treated. Most practi-
tioners and health professionals must be informed about the
existence of medication-overuse headache since the mechan-
isms by which it develops are not fully understood yet,
although structural and functional brain changes play
a definitive role.
Using functional imaging studies may identify those who
are likely to not respond or relapse after treatment. This could
help the choice of the approach, but there is no consensus yet
on the most effective treatments. It is clear, however, that
withdrawal of overused medications and education of the
patients are crucial. We still need better evidence regarding
the time of initiation and choice of pharmacological agents for
prevention, which certainly will improve treatment outcomes
as well as reduce costly procedures. The emerging anti-CGRP
monoclonal antibodies may provide amelioration despite the
persistence of symptomatic medication overuse, but this out-
come still needs greater clinical experience to be confirmed on
real-world patients.
Despite the relapse in certain populations of sufferers, the
prognosis is good. Most will present headache frequency
reduction and decreasing consumption of symptomatic med-
ications after a thorough comprehensive treatment. Finally, we
present six steps, which may guide clinicians approaching
some of these patients and have been successfully used for
decades by the authors of this review:
● Withdrawal suddenly overused medications.
● Provide clear explanations (written and verbal) regarding
MOH.
● Evaluate the prescription of bridge medications for the
initial 5–7 days of withdrawal.
● Evaluate starting prophylactics from the 6th-8th day
onwards.
● Offer psychological/physiotherapeutic accessory treat-
ment and request the initiation of regular physical
activity.
● Reevaluate patients at regular intervals with headache
diaries.
Acknowledgments
The authors wish to thank Dr Fernando Kowacs MD PhD with his help in
suggesting critical issues and checking for overall content with the manuscript.
Funding
This paper was not funded.
Declaration of interest
The authors have no relevant affiliations or financial involvement with any
organization or entity with a financial interest in or financial conflict with
the subject matter or materials discussed in the manuscript. This includes
employment, consultancies, honoraria, stock ownership or options, expert
testimony, grants or patents received or pending, or royalties.
Reviewer disclosures
Peer reviewers on this manuscript have no relevant financial or other
relationships to disclose.
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