CME Features of medication overuse

headache following overuse of different

acute headache drugs
V. Limmroth, MD; Z. Katsarava, MD; G. Fritsche, PhD; S. Przywara, MD; and H.-C. Diener, MD, PhD

AbstractObjective: To investigate pharmacologic features such as mean critical duration until onset of medication-
overuse headache (MOH) (MCDO), mean critical monthly intake frequencies (MCMIF), and mean critical monthly dosages
(MCMD) as well as specific clinical features of MOH after overuse of different acute headache drugs, with a focus on newly
approved triptans. Methods: In a prospective study 98 patients with MOH according to International Headache Society
(IHS) criteria underwent standardized inpatient withdrawal from their medication. Patient diaries and structured inter-
views were used to calculate the MCDO, MCMIF, and MCMD for each substance group. Results: The MCDO was shortest
for triptans (1.7 years), longer for ergots (2.7 years), and longest for analgesics (4.8 years). The MCMIF was lowest for
triptans (18 single doses per month), higher for ergots (37), and highest for analgesics (114). Although patients overusing
ergots and analgesics typically had a daily tension-type headache, patients with triptan-induced MOH were more likely to
describe a (daily) migrainelike headache or an increase in migraine frequency. Conclusion: Overuse of triptans leads to
MOH faster and with lower dosages compared with ergots and analgesics. Clinical features of MOH depend on the type of
overused headache medication. Pharmacologic and clinical characteristics of triptan-induced MOH call for the renewal of
the current IHS classification.
NEUROLOGY 2002;59:10111014

First described in 1951 by Peters and Horton1
medication-overuse headache (MOH, formerly drug-
induced headache) is a frequent, well-characterized
disorder.2 Population-based studies report the preva-
lence rate of MOH to be 1 to 2% in the general
population.3,4
MOH has been defined by the Classification Com-
mittee of the International Headache Society (IHS)
as a constant, diffuse, dull (daily) headache, some-
times of pulsating character and without associated
autonomic symptoms, after the overuse of ergots or
analgesics at more than 15 days per month for at
least 3 months.2 These criteria of the IHS, published
in 1988, were based on experience with ergots and
analgesics as combined drugs (i.e., with caffeine, co-
deine, or barbiturates) and do not cover pharmaco-
logic or clinical characteristics of triptan-induced
MOH. Recently, clinical reports suggest that the
overuse of triptans may lead to the development of
MOH as well.5,6
We previously published 11 cases of triptan-
induced MOH with a clinical presentation different
from the current IHS criteria.7 Nine patients had
migrainelike daily headache or developed a pure
increase of migraine attacks that improved after with-
drawal. In this study, we compared the pharmacologic
and clinical features of MOH after the overuse of
triptans with most of the other acute headache drugs.
Patients and methods. The study was approved by the
ethics committee of the Medical Faculty, University of Es-
sen, Germany. Written consent for the study was obtained
from all patients before withdrawal.
Patients. Ninety-eight patients with MOH (IHS crite-
ria2) were included in the study. Previously, MOH after the
intake of acute headache drugs at 10 days per month was
reported.5 Therefore, patients with more than 10 headache
days per month and intake of any type of acute headache
drug at more than 10 days per month were also admitted
into the study. Symptomatic headaches were excluded by
clinical examination, Doppler and duplex sonography, and
by CT scan or MRI as necessary. Patients with an intake of
more than one substance at more than 5 days per month
were also excluded from the study. Patients underwent
standardized withdrawal as described previously.8 Pa-
tients without improvement of their headache 1 month
after withdrawal were excluded from the study.
Study design. All patients were recruited from the
headache outpatient clinic of the Department of Neurology
in Essen and underwent a detailed (structured) interview
by an experienced neurologist about the history of the pri-
mary headache; all details regarding the development of
MOH, including type of overused drug, dosages, duration,

See also page 972

From the Department of Neurology, University Hospital Essen, Germany.

Z.K. is a fellow of the Hans-Gottschalk-Stiftung in the Stifterverband der Deutschen Wissenschaft.
Received November 19, 2001. Accepted in final form July 14, 2002.
Address correspondence and reprint requests to Dr. Hans-Christoph Diener, Department of Neurology, University Hospital Essen, University of Essen,
Hufelandstr. 55, 45122 Essen, Germany; e-mail: h.diener@uni-essen.de

Copyright 2002 by AAN Enterprises, Inc. 1011

Table 1 Number of patients with different clinical features of
medication-overuse headache and type of overused medication
Analgesics, Ergots, Triptans,
Clinical features N 46 N 12 N 38
Migrainelike daily headache 0 1 10
Increase in migraine frequency 0 1 15
TTH-like daily headache 46 10 13
TTH tension-type headache.
and frequency of drug intake; and the specific clinical fea-
tures of MOH. Patients without clear documentation of
their medication were asked to proceed as usual for at
least 1 month and to document their medication in a diary.
Patients were divided into three groups according to
their primary headache: migraine (MH), tension-type
headache (TTH), and combination of migraine and tension-
type headache (CH). According to the overused drug, pa-
tients were divided to those overusing analgesics (A),
ergots (E), and triptans (T).
The individual critical duration of overuse was calcu-
lated by subtracting the duration of MOH from the dura-
tion of drug overuse and was further used to calculate the
mean critical duration of overuse (MCDO) for each drug
group. Mean critical monthly intake frequencies (MCMIF)
and mean critical monthly dosages (MCMD) were calcu-
lated according to patient diaries for each drug group. The
MCMIF was used to compare the different drug groups
with one another.
Statistical analysis. Pharmacologic differences be-
tween analgesics, ergots, and triptans with regard to
MCDO and MCMIF were examined by the nonparametric
method of the H test (KruskalWallis). Post hoc tests were
performed by pairwise U test. The interdependence of the
nonparametric variables clinical features of MOH and
type of overused medication (tables 1 and 2) or clinical
features of MOH and type of primary headache (tables 3
and 4) is represented in cross tabs. Fishers exact test was
used to calculate the global significance, and post hoc pair-
wise comparisons were used to reveal differences in MOH
features in dependence of drug and headache classes.
Therefore, the level of significance was adjusted to p
0.016. All statistics were calculated with the SPSS pro-
gram (9.0.1).
Results. Patient population. Two of 98 patients did not
report any improvement of their headache 1 month after
withdrawal and were excluded. Among the remaining 96
patients, there were 78 women (81%) and 18 men (19%),
with a mean age of 43 years (range, 23 to 65 years). Sixty-
nine patients (71%) had migraine, 13 patients (14%) had
tension-type headache, and 14 patients (15%) had a combi-
Table 2 Overall and pairwise comparison of clinical features of medication-overuse headache (MOH) between the different groups of
overused drugs
Parameter Overall significance Analgesics vs ergots
Clinical features of MOH 0.0001
Values are expressed as p values.
* Not significant.
1012 NEUROLOGY 59 October (1 of 2) 2002
Table 3 Number of patients with different clinical features of
medication-overuse headache and type of primary headache
MH, CH, TTH,
Clinical features N 69 N 13 N 14
Migrainelike daily headache 9 2 0
Increase in migraine frequency 16 0 0
TTH-like daily headache 44 11 14
MH migraine headache; CH combination headache (mi-
graine and TTH); TTH tension-type headache.
nation of migraine and tension-type headache. Mean dura-
tion of primary headache was 22 years (range, 3 to 44
years). Forty-six patients (48%) overused analgesics, 12
(13%) overused ergots, and 38 (39%) overused triptans.
Mean duration of drug overuse was 6.5 years (range, 0.5 to
25 years).
Pharmacologic characteristics of the overused medica-
tion. The MCDO was the shortest in patients overusing
triptans (1.7 years), longer in patients overusing ergots
(2.7 years), and longest in patients overusing analgesics
(4.8 years; tables 5 and 6). The evaluation of MCMIF re-
vealed 18 single dosages per month for triptans, 37 single
dosages per month for ergots, and 114 single dosages per
month for analgesics (see tables 5 and 6). The MCMD for
each drug are also shown in table 5.
Because only patients with migraine (but not patients
with tension-type headache) used and overused triptans,
MCDO and MCMIF for analgesics, ergots, and triptans
were compared in the subpopulation of migraine patients
only. The findings in this subpopulation were similar to
those observed for the entire patient population. The
MCDO was the shortest for triptans (1.8 years), longer for
ergots (2.6 years), and the longest for analgesics (4.6
years). Again, the MCMIF was the lowest for triptans (18
single doses per month), higher for ergots (36 single doses
per month), and highest for analgesics (114 single doses
per month, see table 6).
Clinical features of MOH and type of overused
drug. All patients overusing analgesics (n 46) devel-
oped a TTH-like daily headache. Of those 12 patients over-
using ergots, 10 patients (83%) developed a TTH-like daily
headache, one patient a migrainelike daily headache, and
one patient an increase in migraine frequency. In contrast,
of the 38 patients overusing triptans, 15 patients (39.5%)
developed an increase in the frequency of their migraine
attacks, 10 patients (26.3%) developed a migrainelike daily
headache, and only 13 patients (34.2%) developed a TTH-
like daily headache. The number of patients with an in-
crease of migraine frequency or migrainelike daily
headache was higher in the triptan group compared to the
ergot and analgesic groups (see tables 1 and 2).
Analgesics vs triptans Ergots vs triptans
0.04* 0.001 0.014
Table 4 Overall and pairwise comparison of clinical features of MOH between patients with different type of primary headache

Parameter Overall significance MH vs TTH MH vs CH CH vs TTH

Clinical features of MOH 0.022 0.022 0.123 0.22

Values are expressed as p values.

p Values were not significant.

MH migraine headache; TTH tension-type headache; CH combination headache (migraine and TTH).

Clinical features of MOH and type of primary headache.
All patients with TTH as their primary headache devel-
oped a chronic TTH-like headache. Patients with migraine
as their primary headache, however, developed different
clinical features: 44 patients (63.7%) developed a TTH-like
daily headache, nine patients (13%) developed a migraine-
like daily headache, and 16 patients (23.3%) developed no
daily headache but had a significant increase in the fre-
quency of migraine attacks compared to the initiation of
regular drug intake (average increase by 5.7 attacks;
range, 3 to 10 attacks). Patients with a combination of
TTH and migraine as their primary headache (n 13)
presented different clinical features as well: 11 patients
(84.6%) developed a TTH-like daily headache and two pa-
tients (15.4%) developed a daily migrainelike headache.
The number of patients with an increase of migraine fre-
quency or migrainelike daily headache was higher in the
migraine group; however, it did not reach significance after
alpha adjustment (see tables 3 and 4).
Discussion. MOH is caused by the overuse of
acute headache drugs and can be avoided by the
restriction of drug use below the drugs specific criti-
cal monthly dosage. Hence, the evaluation of critical
monthly intake frequencies and critical monthly dos-
ages for each drug group as well as the awareness for
initial symptoms of medication overuse may help to
alleviate this fast-growing global problem.
We investigated 96 patients with MOH due to the
overuse of different acute headache drugs. As in
most other studies investigating MOH, the majority
of our patients (81%) were women who had migraine
as their primary headache (71%). About half of our

Table 5 Type of medication, mean critical duration of overuse (MCDO), mean critical monthly intake frequencies (MCMIF), and mean
critical monthly dosages (MCMD)

Drug Patients, n (%) MCDO, y (SD) MCMIF, single doses (SD) MCMD, mg

Analgesics 46 (48) 4.8 (4.9) 113.9 (63.5)

Analgesics 9 (9) 5.2 (5.0) 74.4 (47.5) 37,000
Analgesics caffeine 25 (26) 5.4 (5.1) 135.1 (57.9) 48,774
Analgesics codeine 4 (4) 5.5 (7.0) 129.0 (101.0) 72,550
Metamizol 2 (2) 2.3 (1.9) 34.5 (14.8) 17,250
Opioids 6 (7) 2.2 (2.1) 107.5 (52.3) 7,062
Triptans 38 (40) 1.7 (3.3) 18.6 (7.6)
Sumatriptan 12 (13) 2.4 (3.1) 20.1 (8.3) 1,612
Zolmitriptan 20 (21) 1.7 (3.8) 18.4 (7.5) 46
Naratriptan 5 (5) 0.7 (1.3) 16.5 (7.8) 59
Rizatriptan 1 (1) 0.3 () 15.0 () 150
Ergots 12 (12) 2.7 (2.0) 36.7 (18.1) 53

Table 6 Overall and pairwise comparison of MCDO and MCMIF between the different groups of overused drugs

Parameter Overall significance Analgesics vs ergots Analgesics vs triptans Ergots vs triptans

MCDO-ALL 0.001 0.29* 0.001 0.02*

MCMIF-ALL 0.001 0.001 0.001 0.002
MCDO-MIG 0.001 0.14* 0.001 0.41*
MCMIF-MIG 0.001 0.003 0.001 0.005

Values are expressed as p values.

* Not significant.

MCDO mean critical duration of overuse; MCMIF mean critical monthly intake frequencies; ALL entire patient population;
MIG subpopulation of patients with migraine.
October (1 of 2) 2002 NEUROLOGY 59 1013
patient population overused analgesics, almost 40%
overused triptans, and only a minority overused er-
gots. The overuse of triptans outnumbered the over-
use of ergots by a large margin, which is a clear
difference from the results of previous studies.9-12
This may reflect that despite high costs, triptans
have become widely used (and overused), and sug-
gests that triptans are to become the most important
group of drugs causing MOH. Four of the available
triptans were used in our population. Hence, there is
no doubt that all triptans can cause MOH. This
study, however, was conducted at a specialized head-
ache center, so the possibility of a negative selection
bias cannot be excluded.
The detailed analysis of the pharmacologic fea-
tures in patients overusing triptans revealed a mean
critical intake duration until onset of MOH of 1.7
years and was shown in some patients to be as short
as 6 months. Although the mean critical intake fre-
quency in patients overusing triptans was 18 single
doses per month, it was as low as 10 single doses per
month in some patients, indicating that an intake (of
triptans) every other or even every third day may be
sufficient to develop MOH.
The mean critical monthly dosages for analgesics,
ergots, and sumatriptan in our population were com-
parable with the results from earlier studies.13,14
The detailed evaluation of clinical features of
MOH further revealed that unlike other drugs, the
majority of migraine patients overusing triptans de-
velop a migrainelike daily headache or an increase of
migraine attack frequency without experiencing a
daily-occurring headache. After withdrawal, how-
ever, even patients with only an increase in attack
frequency reported a significant reduction of their
migraine attacks. This suggests that this increase in
migraine attack frequency was caused by the over-
use of triptans and therefore should be considered a
triptan-specific form of MOH.
Taken together, the study suggests that the phar-
macologic and clinical presentation of triptan-
induced MOH is different from that induced by other
acute headache drugs such as ergots and analgesics.
The data indicate that 10 single dosages per month
may be sufficient to cause MOH and therefore should
be considered a critical threshold. The study further
suggests that an increase in the frequency of mi-
1014 NEUROLOGY 59 October (1 of 2) 2002
graine attacks may be considered a triptan-specific
form of MOH that would require a temporary discon-
tinuation of the drug.
Although it has been recently shown that with-
drawal from triptans is shorter and easier compared
to ergots and analgesics,8 it seems useful to restrict
the intake of triptans to a maximum of 10 single
dosages per month. Finally, the study calls for a
renewal of the current IHS criteria for MOH, which
does not cover the specific clinical features of triptan-
induced MOH.
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