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Medication Overuse Headache

ARTICLE in CURRENT OPINION IN NEUROLOGY JULY 2004
Impact Factor: 5.31 DOI: 10.2165/00002018-200124120-00005 Source: PubMed

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NU170304

Medication overuse headache

Volker Limmroth and Zaza Katsarava
Purpose of review
The current literature on medication overuse headache will be
reviewed with regard to clinical presentation, pathophysiology,
therapy and prognosis in the light of the new headache
classification.
Recent findings
Medication overuse headache is a widely unrecognized medical
condition, which according to recent epidemiological studies
has evolved to the third most frequent form of headache after
tension-type headache and migraine. The first classification of
headache disorders from 1988 defined medication overuse
headache (formerly called drug-induced headache) on the
bases of drugs that were available in the 1980s. For the most
important anti-headache drugs, including triptans, new data on
specific clinical features and more important mean critical
monthly dosages and mean critical monthly intake frequencies
are now available. Furthermore, recent prospectively conducted
studies have revealed rates and predictors of relapse after
successful withdrawal.
Summary
The newly available data on medication overuse headache may
provide the basis for future consensus guidelines for the
management of this condition.
Keywords
Analgesics, chronic headache, ergots, medication overuse,
migraine, triptans
Curr Opin Neurol 17:000000.

2004 Lippincott Williams & Wilkins.

Department of Neurology, University Hospital Essen, Essen, Germany

Correspondence to Volker Limmroth, MD, PhD, Department of Neurology, University
Hospital Essen, Hufelandstrasse 55, 45122 Essen, Germany
Tel: +49 201 723 2495; fax: +49 201 723 5176;
e-mail: volker.limmroth@uni-essen.de
Current Opinion in Neurology 2004, 17:000000
Abbreviations
CDH
5-HT
IHS
MOH
TTH

chronic daily headache

5-hydroxytriptamine
International Headache Society
medication overuse headache
tension-type headache

2004 Lippincott Williams & Wilkins

1350-7540
#

DOI: ?????????????????

Introduction
A variety of different names has served to describe the
phenomenon in which the frequent use of anti-headache
medication can either worsen the initial headache
disorder or even create a new form of daily appearing
headache. As a result of a missing definition before the
first International Headache Society (IHS) classification
in 1988 [1], which used the term drug-induced headache, several different terms were used to describe the
same entity. Among the most frequently used terms are:
chronic migraine, daily headaches, transformed migraine,
drug-induced headache, painkiller headache, medication
misuse headache, medication overuse headache (MOH),
analgesic-dependent headache, or analgesic overuse
headache. These terms mostly reflected the clinical
presentation of the additional headache. The clinical
picture may vary a great deal, and depends greatly on the
underlying primary headache and the type of drug that is
overused. Some of these terms now represent different
clearly defined headache disorders according to the new
IHS classification [2 . .] that was introduced in 2003. As
almost all types of drugs for the treatment of primary
headaches may cause headache or worsen the initial
underlying headache, and as the term should indicate
that the headache is caused by frequent intake (rather
than being caused directly, as seen with nitrates, for
example) the committee of the new headache classification decided to introduce the term medication overuse
headache. According to the new classification, MOH can
be diagnosed when the following criteria are fulfilled:
headache on 15 or more days a month; pain characteristics are bilateral, dull, and of light to moderate
intensity; drug intake includes ergots, triptans and
opioids for 10 or more days per month, analgesics 15
days or more for a minimum of 3 months (the new
classification now clearly distinguishes between the
different types of drugs); and the headache disappears
after withdrawal.

Epidemiology of analgesic and triptan

overuse
In many countries, analgesic overuse is very common in
the general population. Early studies in the 1980s and
1990s estimated that approximately 1% of the German
population takes up to 10 analgesic tablets every day [3].
In Switzerland, a study of a representative sample of the
Swiss population revealed that approximately 4.4% of
men and 6.8% of women took analgesics once a week or
more and 2.3% took them daily [4]. In Norway, a study
of over 19 000 individuals showed that 28% of men and
13% of women had used analgesics over the preceding
1

Headache

28-day period, mostly to treat headaches [5]. A recent

cross-sectional population-based epidemiological study
in Norway (Head-Hunt study) including almost 50 000
subjects revealed that approximately 10% of this
population reported taking analgesics currently on a
daily basis. Up to 5% reported taking analgesics on a
daily basis for at least 6 months [6 . .].
Not only over-the-counter-type analgesics are widely
overused. There is convincing evidence that 5-hydroxytriptamine (5-HT) agonists (triptans) have recently
also become widely overused. In a UK study of 360
migraine patients, 7% of patients used more than 150
doses of triptans over a 12-month period [7]. These
results confirmed observations from an audit of sumatriptan use in Denmark in 19941995 [8,9], which
showed that 5.1% of migraine patients took an average
of one or more doses per day. Furthermore, a review of
the first 27 months of sumatriptan treatment in Denmark
showed that 1% of patients accounted for 20% of the
total consumption [10]. The main question for cohorts
like this, however, is what percentage of these medication overusers will develop MOH. This question was
recently addressed by prospective study on patients with
migraine. The cohort consisted out of over 600
consecutive migraine patients without MOH or chronic
daily headache (CDH) who were followed up for 12
months [11]. Some 14% of the cohort developed CDH
within one year and two-thirds of these fulfilled the
criteria for MOH. The two main predictors were a high
frequency of headache events initially and medication
overuse.

Epidemiology of medication overuse

headache
Without doubt, tension-type headache (TTH; experienced by 50% or more of the population) and migraine
(experienced by 1012%) are the most frequent forms of
primary headache. Only a few reliable trials have
investigated the incidence and prevalence of medication-induced headache. Some recent studies have
suggested a prevalence for CDH of between 2 and 4%
in the general population of France [12]. However, the
term chronic daily headache is not clearly defined and
may cover chronic TTH and chronic migraine as well as
MOH.
The Head-Hunt study [6 . .] revealed a prevalence for
MOH of over 1% in a Norwegian cohort. Another
population-based study on CDH recently conducted in
Spain indicated that 1% of the general population
suffered from daily headache combined with medication overuse [13]. In the USA, a study in primary care
indicated that MOH was the third most common cause
of headache [14]. In European speciality headache
clinics, up to 10% of patients may have MOHs, and

patients are often taking multiple headache medications [15]. A recent Norwegian study further suggested
that a low socioeconomic status is associated with an
increased risk of developing frequent and chronic
headaches [16].
MOH is not only a problem of European or north
American countries, but appears to be a global phenomena. An epidemiological study in a population of elderly
Chinese individuals (465 years) revealed an incidence
of 3.9% for CDH in combination with the overuse of
anti-headache medication [17]. Similar results were
obtained from a study recently conducted in Taipei,
Taiwan, on 3377 subjects [18]. Within that cohort, 3.2%
suffered from daily headache and third of those fulfilled
the IHS criteria of MOH.
More frightening, however, is growing evidence that
MOH is not only a problem of adults, but rather of
adolescents and even children [19]. A recent study on
caffeine-induced headache in children revealed that
MOH may occur in children as young as 6 years [20]. At
this point, the children had already suffered on average
over 12 months, indicating that the overuse had started
between the ages of 4 and 5 years. Data on the
prevalence of MOH in children are not available yet,
but the fact that there are the first reports on MOH
withdrawal therapy in children clearly demonstrate the
rising problem [20,21], and may indicate that one has to
expect an increase in the prevalence of MOH in adults
in the future.
Taken together, the prevalence of CDH appears to be
between 2 and 4% in the general population. MOH
accounts for approximately a third of these cases,
indicating a prevalence of approximately 1% of the
general population globally.

Clinical presentation of medication overuse

headache
As outlined by the old classification of the IHS [1],
MOH as a result of the overuse of analgesics, mostly
combination preparations or ergots, presents with a
chronic, holocranial, diffuse, dull headache without
associated symptoms. In addition, ergotamine-induced
headache can also appear as a diffuse headache with a
pulsating character.
In a meta-analysis by Diener and Dahlof in 1999 [22]
including 2612 patients with MOH, migraine was the
primary headache in 65% of patients, TTH in 27% and
combined or other headaches in 8%. More than three
times as many women as men had MOH in their analysis
(3.5 : 1). Patients suffered on average for 10.3 years from
their primary headache, with a mean duration of daily
headache of 5.9 years.

Medication overuse headache Limmroth and Katsarava

The definitions in the first classification and the

aforementioned meta-analysis were based on studies
and experience with analgesics and ergots only. Soon
after the approval of sumatriptan and other members of
the triptan family it became evident that as with
analgesics and ergots all triptans could also cause MOH
[23,24]. Clinically, however, patients suffering from
MOH as a result of triptan overuse presented with
different features than those suggested by the old IHS
classification. Not only do triptans appear to cause
migraine-like daily headache (as opposed to tensiontype-like headache) but also cause a pure increase in
migraine attack frequency [24] without necessarily
causing daily headache. In a prospective study, Limmroth et al. [25] examined 98 consecutive patients and
evaluated clinical features as well as pharmacological
features, such as the mean critical duration of overuse,
the mean critical monthly intake frequency, and the
mean critical monthly dosage, as well as specific clinical
features of MOH after the overuse of different acute
headache drugs with a focus on newly approved triptans.
Interestingly, the mean critical duration of overuse was
shortest for triptans (1.7 years), longer for ergots (2.7
years), and longest for analgesics (4.8 years). The mean
critical monthly intake frequency was lowest for triptans
(18 single doses per month), higher for ergots (37 doses),
and highest for analgesics (114 doses). Whereas patients
overusing ergots and analgesics typically suffered from a
daily TTH, patients with triptan-induced MOH were
more likely to describe a (daily) migraine-like headache
or an increase in migraine frequency. Therefore, the
overuse of triptans led to MOH faster and with lower
dosages compared with ergots and analgesics, and the
clinical features of MOH obviously depended on the
type of overused headache medication. Consequently,
the pharmacological and clinical characteristics of triptaninduced MOH called for the renewal of the first IHS
classification.

Pathophysiology
The underlying pathophysiology of MOH is still unclear.
As in most of the headache entities, several different
aspects, such as genetic background, peripheral and
central receptor regulation, specific psychotrophic effects
and behavioural conditioning, appear to play key roles.
Genetics

Because only patients suffering from migraine or TTH,

but not patients with cluster headache, are known to
develop MOH as a result of the overuse of their
medication, genetic determination appears to be important. This is supported by the observation that
patients with other chronic painful disorders such as
rheumatoid arthritis, who are known to consume
analgesics, mostly in high dosages on a regular basis,

are not known to develop MOH. Interestingly, patients

with a past history of migraine, however, who are forced
to take analgesics on a regular basis for other painful
(non-headache) disorders may develop MOH [26 .].
There are therefore several aspects suggesting a specific
genetic susceptibility for patients with migraine or TTH
to develop MOH.
Psychotropic effects

Some well-established anti-headache compounds, especially in countries outside the European Union, contain
substances with psychotropic effects such as caffeine,
codeine or barbiturates. An international consensus
paper on the dependence of caffeine, however, came
to the conclusion that there was no firm evidence to
support there being a clear role for caffeine in the
development of MOH [27]. However, there is no doubt
that caffeine possesses a synergistic analgesic effect,
reduces fatigue, increases vigilance, and improves
cognitive performance. After its consumption in high
dosages over days and weeks, the fall in the blood
concentration of caffeine may cause the opposite effects
such as tiredness, difficulties in concentration or
caffeine-withdrawal headache, which disappears again
after re-exposure. It goes without saying that this
mechanism encourages the patient to reinstate their
regular drug intake. As there is growing evidence for a
genetic predisposition in patients suffering from migraine or TTH to develop MOH, it is likely that these
patients react differently on caffeine (e.g. developing
withdrawal symptoms at lower dosages) than the average
population. At least 10% of codeine (methylmorphine) is
demethylized to morphine by the liver. Codeine may
thus lead to physical dependency like other opioid, and
with a vicious circle of withdrawal symptoms and
increasing intake frequency.

Peripheral and central regulation

As discussed above, there is a body of evidence to
suggest that the overuse of different drugs will cause
MOH with different clinical features in different timeframes [25], e.g. triptans cause MOH significantly faster
than analgesics. In addition, a study on withdrawal
headache [28] observed that withdrawal symptoms lasted
significantly longer when analgesics were overused
compared with triptans or ergots. The conclusion from
these observations is that the development of MOH as
well as the duration and intensity of withdrawal
symptoms depend primarily on the mechanism of action
of the particular group of drugs. Triptans act via 5-HT1
receptors, which are all G-protein-coupled receptors.
Analgesics, on the other hand, act via the inhibition of
prostaglandin synthesizing enzymes, such as cyclooxygenase I or II. 4From receptor physiology, it is well
known that the downregulation of 5-HT receptors may
occur as early as 2496 h after chronic exposure [29].

Headache

Recently, it has been shown in animals that chronic

treatment with triptans such as sumatriptan or zolmitriptan will cause a significant downregulation of 5HT1B/D receptors within the cortex and the brainstem
[30 .]. Thus it is likely that chronic or frequent exposure
to 5-HT1B/D agonists may lead to a downregulation of 5HT receptors and may subsequently change central
inhibitory (and anti-nociceptive) pathways. Furthermore,
regulation of receptors within pain processing structures
is likely to occur significantly faster than the change in
enzyme activity after chronic analgesic overexposure and
would explain the different kinetics for the development
of MOH and for withdrawal symptoms seen in patients
with triptan- or analgesic-induced-MOH.

Management of medication overuse

headache
There is general agreement that the only treatment for
MOH is withdrawal therapy. However, very few
prospective studies have investigated the treatment of
MOH or the effectiveness of medication withdrawal. As
indicated by a recent prospective study on withdrawal
therapy [28], withdrawal symptoms will vary greatly in
clinical presentation and intensity according to the drug
that has been overused. Although withdrawal from
triptans is mostly short (approximately 80% of patients
are without headache 4 days after initiating withdrawal
therapy, but less than 20% report being headache free at
this timepoint when analgesics were overused) and
without intensive withdrawal symptoms, withdrawal
from ergot and combination analgesics may cause
nausea, vomiting, hypotension and tachycardia for
several days. Subsequently, the accompanying medication to alleviate withdrawal symptoms should be
selected accordingly.
Treatment of withdrawal symptoms

Although withdrawal from triptans does not usually

require additional medication to reduce withdrawal
symptoms, fluid replacement, anti-emetics, mono-analgesics, or even clonidine and beta blockers may be
required for the withdrawal of ergots or combination
analgesics. A recently conducted open study showed that
cortisone reduced withdrawal symptoms, including the
withdrawal headache [31], which needs to be confirmed
by larger trials. A recent study indicated some benefit of
ascending doses of alpha2-agonist tizanidine in combination with a long-acting non-steroidal anti-inhibitory drug
for treatment withdrawal symptoms [32]. Older openly
conducted but randomized studies suggested that
naproxen may be better than anti-emetics and other
analgesics for acute treatment [33], and that sumatriptan
can be helpful to treat withdrawal symptoms during
ergot withdrawal [34]. Until now there are no guidelines
or consensus recommendations about accompanying
medication during withdrawal therapy. An important

issue, however, is whether withdrawal therapy should be

carried out on an inpatient or outpatient basis. On this
issue, the German Migraine and Headache Society has
provided consensus recommendations: highly-motivated
patients who are not using barbiturates and tranquillizers
(benzodiazepines) and who receive a tight follow-up
(daily or almost daily in the first 10 days) from their
physicians may be treated as outpatients. Patients who
overuse drugs containing codeine, barbiturates or tranquillizers, those who are depressed or who have failed
previously to withdraw as outpatients should be treated
under hospital conditions [35].
Long-term treatment of medication overuse headache

There is some debate about whether prophylaxic or

long-term treatment should be initiated immediately at
or after withdrawal therapy. Clinically, it is well known
that long-term treatment does not work during drug
overuse. After withdrawal therapy, most patients will
experience the same frequency of migraine attacks they
used to have before drug overuse. Therefore, patients
who suffered initially from a low frequency of migraine
attack or few headache days per month might not even
need prophylactic medication. The majority of patients,
however, will need long-term medication, which if the
initial headache frequency was high should be started
during withdrawal therapy. Interestingly, a recent prospectively conducted one year follow-up study on
patients who underwent withdrawal therapy [36 .]
revealed that the initiation of long-term or prophylactic
treatment did not influence the rate of relapses within
the first year after withdrawal therapy. The only
significant predictors in this cohort of 90 patients were
the underlying primary headache and the drugs that
were overused. It is absolutely essential that patients
after withdrawal receive a concept of how to deal with
their headache attacks, that they keep a headache diary,
and that they know the maximal monthly dosages they
are allowed to take per month in the future [25]. Critical
monthly intake frequencies and critical monthly dosages
are displayed in Table 1.

Prognosis of medication overuse headache

Several studies investigated the prognosis of MOH,
especially relapse rates and possible predictors of
relapses. Most of these studies, however, have been
conducted retrospectively. Recent retrospective studies
from Austria and Germany suggested relapse rates
between 32.7% (within 5 years) [37] and 48% (within 4
years) [38]. A large prospective study indicated a relapse
rate of 38% within the first 12 months after withdrawal
[36 .] and of 42% after 4 years [39]. These data were
generated in the identical cohort, which suggested that
the first 12 months were the most critical period. In other
words, patients who remained relapse free within the
first 12 months were highly likely to stay relapse free for

Medication overuse headache Limmroth and Katsarava

Table 1. Type of medication, mean critical duration of overuse, mean critical monthly intake frequencies, and mean critical monthly dosages
Drug
Analgesics
Analgesics
Analgesics + caffeine
Analgesics + codeine
Metamizol
Opioids
Triptans
Sumatriptan
Zolmitriptan
Naratriptan
Rizatriptan
Ergots

Patients
N (%)

MCDO
m (SD)

46
9
25
4
2
6

(48)
(9)
(26)
(4)
(2)
(7)

4.8
5.2
5.4
5.5
2.3
2.2

(4.9)
(5.0)
(5.1)
(7.0)
(1.9)
(2.1)

38
12
20
5
1
12

(40)
(13)
(21)
(5)
(1)
(12)

1.7 (3.3)
2.4 (3.1)
1.7 (3.8)
0.7 (1.3)
0.3 (7)
2.7 (2.0)

MCMIF
m (SD)
113.9
74.4
135.1
129.0
34.5
107.5

MCMD
mg

(63.5)
(47.5)
(57.9)
(101.0)
(14.8)
(52.3)

18.6 (7.6)
20.1 (8.3)
18.4 (7.5)
16.5 (7.8)
15.0 (7)
36.7 (18.1)

37 000
48 774
72 550
17 250
7062

1612
46
59
150
53

MCDO, mean critical duration of overuse; MCMIF, mean critical monthly intake frequency; MCMD, mean critical monthly dosage.
Reproduced with permission from Limmroth et al. [25].

the next few years. Because of the great number of

patients in the study, the authors were able to examine
subgroups of patients and found that the relapse rate
mainly depended on two factors: the primary headache
disorder and the type of drug that was overused. Patients
with TTH had a significantly higher relapse rate than
patients with migraine (73 versus 22%, respectively).
Moreover, patients who initially overused analgesics
(mostly combination analgesics) showed significantly
higher relapse rates than patients overusing ergots or
triptans (58 versus 22 versus 19%, respectively for the
first 12 months). Interestingly, other predictors such as
the duration of drug overuse, the duration of disorder,
the presence of prophylactic treatment, etc. did not
influence the relapse rate (neither within the first 12
months nor within 48 months). These data, however,
were important for another reason: they suggested that
the overall results of studies investigating relapse rates
after withdrawal mainly report different results because
of a different patient population. Therefore, studies with
a high percentage of patients with migraine and triptan
or ergot overusers will show better results than studies
with a high percentage of TTH, patients who overuse
combination analgesics.

Conclusion
MOH is a medical condition with a high prevalence of
approximately 1% within the general population all over
the world. The prevalence is likely to increase because
there is an increasing number of reports on MOH in
adolescence and even early childhood. MOH can be
caused by almost all anti-headache drugs, including
analgesics, ergots, triptans and medications containing
barbiturates, tranquillizers, codeine and caffeine. The
duration of drug overuse and the necessary dosages for
the development of MOH vary significantly, and clearly
depend on the substance that is overused [25]. The new
5-HT1B/D agonists in particular may induce MOH fast

and at low dosages. Withdrawal is the only successful

treatment concept for MOH. Again, the duration and
intensity of withdrawal and its subsequent success
depend on the primary headache and the substance that
is overused. Patients with TTH as the primary headache
and patients overusing analgesics not only suffer from
significantly stronger withdrawal symptoms, but also
present with a significantly higher relapse rate [28,36 .].
The only strategy to reduce the prevalence of MOH is to
prevent the development of MOH in the first place.
Anti-headache drugs have to be restricted to a maximal
monthly dosage. The constant education of patients
about the advantages and dangers of anti-headache drugs
by the neurologist, and even more important the primary
care physician, is therefore mandatory [40].

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