Blackwell Publishing LtdOxford, UKCHACephalalgia0333-1024Blackwell Science, 20062006261011921198Original ArticleDiscontinuation of medication overuse in headache patientsP Zeeberg et al.

doi:10.1111/j.1468-2982.2006.01190.x

Discontinuation of medication overuse in headache patients:

recovery of therapeutic responsiveness
P Zeeberg, J Olesen & R Jensen
Danish Headache Centre, Department of Neurology, University of Copenhagen, Glostrup Hospital, Glostrup, Denmark

Zeeberg P, Olesen J & Jensen R. Discontinuation of medication overuse in head-

ache patients: recovery of therapeutic responsiveness. Cephalalgia 2006; 26:1192
1198. London. ISSN 0333-1024
It is generally accepted that ongoing medication overuse nullies the effect of
prophylactic treatment, although few data support this contention. We set out to
describe the treatment outcome in patients withdrawn from medication overuse
and relate any improvement to a renewed effect of prophylaxis. For patients with
probable medication-overuse headache (pMOH), treated and dismissed from the
Danish Headache Centre in 2002 and 2003, we assed, from prospective headache
diaries, the headache frequency before and after withdrawal of offending drugs
and compared these frequencies with the headache frequency at dismissal. Among
1326 patients, 337 had pMOH. Eligible were 175, mean age 49 years, male/female
ratio 1 : 2.7. Overall, there was a 46% decrease in headache frequency from the
rst visit to dismissal (P < 0.0001). Patients with no improvement 2 months after
complete drug withdrawal (N = 88) subsequently responded to pharmacological
and/or non-pharmacological prophylaxis with a 26% decrease in headache fre-
quency as measured from the end of withdrawal to dismissal (P < 0.0001). At
dismissal, 47% were on prophylaxis. Former non-responders to medical prophy-
laxis had a 49% decrease in headache frequency from rst visit to dismissal
(P < 0.0001), whereas those who had never received prophylaxis had a 56% reduc-
tion (P < 0.0001). This difference was not statistically signicant (P = 0.22). Almost
all MOH patients benet from drug withdrawal, either just from the withdrawal
or by transformation from therapeutic non-responsiveness to responsiveness.
According to the International Classication of Headache Disorders, 2nd edn, the
MOH diagnosis requires improvement after drug withdrawal. Our data suggest
that these diagnostic criteria are too strict.
Medication overuse, medication-
overuse headache, medication withdrawal, prophylactic treatment, treatment outcome
Peter Zeeberg MD, Danish Headache Centre, Department of Neurology, University of
Copenhagen, Glostrup Hospital, Nordre Ringvej 57, DK-2600 Glostrup, Denmark.
Tel. + 45 4323 3071, fax + 45 4323 3839, e-mail peter.zeeberg@dadlnet.dk Received 8
February 2006, accepted 21 April 2006

unchanged (48%) and a small group of 7% which

Introduction
deteriorated. This was perhaps a smaller percentage
Overuse of acute migraine medication and plain of improvement than had been expected from the
analgesics is a well-known problem which has been previous literature (68) and the issue therefore was
described repeatedly over the last several decades whether or not there are other benets to the patients
(14). In a recent study, we conrmed that patients who did not improve merely by discontinuation of
with overuse improve simply by being kept medica- the overused drug. In the absence of data, it is
tion free for 2 months (5). While this was the overall generally accepted that patients are refractory to
result, patients segregated clearly into three groups: prophylactic treatment while having medication
one with improvement (45%), one that stayed overuse and that they become responsive after

1192 Blackwell Publishing Ltd Cephalalgia, 2006, 26, 11921198

 Discontinuation of medication overuse in headache patients
medication withdrawal. The primary aim of the
present study was therefore to describe the treat-
ment outcome of patients withdrawn from medica-
tion overuse after initiation of pharmacological and/
or non-pharmacological prophylactic treatment. The
secondary aim was to relate improvement to a
renewed effect of prophylactic medication. We fol-
lowed up at dismissal a previously published study
of patients from the Danish Headache Centre (DHC)
(5) who were kept medication free for 2 months and
analysed the response of these patients to prophy-
lactic treatment. Our hypothesis was that this group
of severely affected patients, previously totally
refractory to treatment at other clinics, would
become responsive to therapy after withdrawal.
Materials and methods
DHC is a tertiary out-patient referral Headache Cen-
tre. It functions as the only national referral centre
for severely affected headache patients in Denmark
(5.4 million inhabitants). At the time of this study,
only referrals made by neurologists were accepted.
All patients dismissed from DHC in 2002 and 2003
had been mailed a diagnostic headache diary 1
2 months before the rst visit. For the present study
diaries were available for 83% of the patients. Ques-
tionnaires recorded by the doctor at the nal visit
describing headache frequency and medication use
at dismissal were also available. Diagnoses, head-
ache frequency and medication use were determined
from these prospective recordings and loaded into a
Microsoft Access 2002 database together with infor-
mation on socio-economic status and previous phar-
macological and non-pharmacological treatment.
The patients were primarily diagnosed according to
International Classication of Headache Disorders
(ICHD)-I, but data allowed a subsequent reclassi-
cation according to ICHD-II.
After establishment of a diagnosis of probable
medication-overuse headache (pMOH) (9), all acute
headache medication was discontinued abruptly
and patients were kept medication free for 2 months
as part of the general treatment programme in DHC
(10). In the case of severe opioid overuse, phenobar-
bital substitution was used for a short period to
avoid abstinence syndromes. Overuse of barbitu-
rates or benzodiazepines must be tapered slowly, but
marked overuse of these substances was not docu-
mented among our patients. Levomepromazine or
promethazin was allowed as the only rescue medi-
cation during withdrawal, primarily to be used for
the rst week. After withdrawal, headache fre-
quency was reassessed and diagnoses were revised.
Blackwell Publishing Ltd Cephalalgia, 2006, 26, 11921198
1193
At this time medical and/or non-medical prophylac-
tic treatment was initiated if needed and symptom-
atic medication was resumed, but with a strict upper
limit of maximally 6 days per month as agreed by
the patient. As part of the non-pharmacological
treatment strategy, patients with signicant pericra-
nial muscle tenderness were referred to physiother-
apy and referral to a psychologist was initiated if
comorbid psychiatric disorder was suspected, if
pharmacological treatment was insufcient or if the
patient expressed specic interest in psychological
treatment.
Statistics
Based on their primary headache diagnoses, the
eligible patients were divided into four groups:
migraine, tension-type headache (TTH), mixed
migraine and TTH (MT) and other diagnoses (OD).
Wilcoxons signed rank test was used for paired
comparisons of headache frequencies within groups.
All comparisons between groups have been
adjusted for variations in the initial headache
frequency using a stratum-adjusted KruskalWallis
test. Post hoc tests were performed using a stratum-
adjusted KruskalWallis test with the step-down
Bonferroni method of Holm adjustment for multiple
testing. P-levels < 0.05 (two-tailed) were chosen as
the level of signicance. Statistical analysis was per-
formed using SAS version 8.2 (SAS Inc., Cary, NC,
USA). Mean values are presented with median val-
ues in parentheses and range in square brackets.
Results
Among 1326 patients treated and dismissed from
DHC in 2002 and 2003, we identied 337 (25%) with
an initial diagnosis of pMOH. We excluded 121 who
did not stay medication free for 2 months, leaving
216 patients of whom 45% had a reduction in
headache frequency by mere discontinuation of the
offending drug, 48% were unchanged following
withdrawal and 7% had an aggravation (5). Among
these 216 patients, 39 were later administratively dis-
missed because of failure to appear and for two
patients information regarding headache frequency
at dismissal was missing, leaving 175 patients eligi-
ble for the present study. The excluded patients were
slightly younger (mean age 44 years vs. 49 years)
and a smaller proportion overused ergots/triptans
(14% vs. 26%). There were no signicant differences
between excluded and enrolled patients with regard
to sex, primary headache diagnoses or initial head-
ache frequency.
1194 P Zeeberg et al.

Among the 175 enrolled patients there were 47

Relative reduction in

30 (12) [ 56100]***

55 (67) [ 67100]***

46 (59) [ 67100]***
headache frequency

39 (20) [ 32100]**
from initial visit to
men (27%) and 128 women (73%) with a mean age

64 (75) [0100]***
of 49 years (range 1786 years). Seventeen patients

dismissal, %
(10%) had migraine, 58 (33%) had TTH, 79 (45%) had
mixed migraine and TTH and 21 patients (12%) had
other headache diagnoses, where post-traumatic
headaches, which had markedly worsened during
overuse, accounted for the majority (N = 12). All
diagnostic groups had a signicant decrease in head-
ache frequency from rst visit to dismissal. Overall,

dismissal, N (%)
prophylaxis at
the mean headache frequency at rst visit was
27 days/month (range 1530 days/month) and at

Medical
dismissal 15 days/month (range 030 days/month).

6 (35)

19 (33)

44 (56)

13 (62)

82 (47)
This corresponds to an overall decrease in headache
frequency from rst visit to dismissal of 46%
(P < 0.0001) (Table 1). The average time from the end
of withdrawal to dismissal was 228 days (range 0

20 (27) [030]

17 (23) [030]

15 (10) [030]
1422 days) for all patients. Figure 1 illustrates the

At dismissal

9 (6) [030]

12 (8) [030]
development in headache frequency from the rst
visit through the end of medication withdrawal to

Headache frequency (days/month)

dismissal for all patients. Table 1 Clinical characteristics and treatment results for all patients withdrawn from medication overuse
Eighty-eight patients (50%) had no initial decrease
in headache frequency following medication with-
drawal. Four patients (5%) had migraine, 37 (42%)

23 (30) [030]

18 (15) [130]

26 (30) [030]

20 (24) [030]
11 (6) [030]
had TTH, 29 (33%) had mixed migraine and TTH withdrawal
and 18 patients (20%) had other headache diagnoses.
All diagnostic groups had a signicant decrease in
After

headache frequency from the end of withdrawal to

dismissal, except for pure migraine where the trend
was the same but not signicant, probably due to

Mean values, median values in parentheses and range in square brackets.

the small number. Overall, the mean headache fre-
23 (22) [1630]

29 (30) [1830]

27 (30) [1530]

29 (30) [1730]

27 (30) [1530]
quency after withdrawal was 29 days/month (range
1930 days/month) and at dismissal 22 days/month
Initial

(range 030 days/month). This corresponds to an

overall decrease in headache frequency from the end
of withdrawal to dismissal of 26% (P < 0.0001)
(Table 2). Comparing migraine, TTH, MT and OD,
47/128

the reduction in frequency differed signicantly

28/30

11/68
M/F

2/15

6/15

between the diagnostic groups (P = 0.022). Post hoc

Sex,

analysis showed a signicantly smaller reduction in

TTH than in migraine and TTH (P = 0.041) and other
diagnoses (P = 0.047). All other comparisons were
48 (52) [2367]

52 (50) [1986]

48 (51) [1774]

48 (48) [2873]

49 (50) [1786]

insignicant. The average time from the end of with-

drawal to dismissal was 249 days (range 0690 days)
TTH, Tension-type headache.

for the non-improving group. Figure 2 illustrates the

years
Age,

development in headache frequency from the rst

**P < 0.001; ***P < 0.0001.

visit through the end of withdrawal to dismissal for

the patients who experienced no initial effect of med-
ication withdrawal.
Migraine + TTH

Other diagnoses

Those 87 patients (50%) who did improve follow-

(N = 17, 10%)

(N = 58, 33%)

(N = 79, 45%)

(N = 21, 12%)

ing the initial 2 months medication withdrawal had

Migraine

(N = 175)

a slight further improvement from the end of

withdrawal to dismissal with an overall additional
Total
TTH

mean reduction of 2 days/month (P < 0.01). For the

Blackwell Publishing Ltd Cephalalgia, 2006, 26, 11921198

 Discontinuation of medication overuse in headache patients 1195

specic diagnostic groups the reduction was signif-
icant only for mixed migraine and TTH (P = 0.003).
The average time from the end of withdrawal to
dismissal for these patients was 207 days (range 0
1427 days).
Overall, 69% of the patients received preventive
medication following withdrawal. Due to either
intolerance or lack of effect the treatment was abol-
ished for some of the patients. At time of dismissal,
47% of our patients were on medical prophylactic
treatment (Table 1) and 44% had a history, before
admission to DHC, of prior medical prophylaxis
without effect, with an average of 1.6 (15) drugs
with different medical proles (antiepileptics, -
blockers, non-steroidal anti-inammatory drugs, Ca-
antagonists, antidepressants, others). In order to
elucidate a possible renewed effect of medical pro-
phylaxis after medication withdrawal, we divided
the patients on prophylactic treatment at dismissal
into two groups based on whether or not they had
received prior medical prophylaxis without effect.
The mean relative reduction in headache frequency
from rst visit to dismissal was 49% (P < 0.0001) for
the known non-responders to medical prophylaxis
and 56% (P < 0.0001) for those who had never

30 30

25 25 *
*
20 20
Days/month
Days/month

*
15 15

10 10

5 5

0 0
Initial After withdrawal Dismissal Initial After withdrawal Dismissal

Figure 1 Development in headache frequency for patients Figure 2 Patients with medication overuse and no
withdrawn from medication overuse (N = 175). , Headache improvement in headache frequency following a 2-month
frequency. *P < 0.0001. drug-free period (N = 88). , Headache frequency. *P < 0.0001.

Table 2 Treatment results for patients with medication overuse and no improvement in headache frequency following a 2-month
drug-free period

Relative reduction
in headache frequency
Headache frequency (days/month) Medical prophylaxis from after withdrawal
Initial After withdrawal At dismissal at dismissal,N (%) to dismissal, %

Migraine (N = 4, 5%) 25 (26) [1830] 28 (28) [2630] 17 (17) [430] 1 (25) 41 (41) [084]
TTH (N = 37, 42%) 29 (30) [1930] 30 (30) [2330] 26 (30) [030] 15 (41) 13 (0) [0100]*
Migraine + TTH 28 (30) [1830] 29 (30) [1930] 18 (24) [030] 16 (55) 36 (22) [ 40100]**
(N = 29, 33%)
Other diagnoses 29 (30) [1730] 30 (30) [2330] 20 (25) [430] 11 (61) 32 (13) [087]*
(N = 18, 20%)
Total (N = 88) 29 (30) [1730] 29 (30) [1930] 22 (30) [030] 43 (49) 26 (0) [ 40100]***

Mean values, median values in parentheses and range in square brackets.

*P < 0.01; **P < 0.001; ***P < 0.0001; not signicant.
TTH, Tension-type headache.

Blackwell Publishing Ltd Cephalalgia, 2006, 26, 11921198

1196 P Zeeberg et al.
Table 3 Patients withdrawn from medication overuse and on medical prophylactic treatment at dismissal
Headache frequency (days/month)
Initial
Prior medical prophylaxis without 27 (30) [1830]
effect before admission (N = 43)
No prior medical prophylaxis 29 (30) [2230]
before admission (N = 37)
Total (N = 80) 28 (30) [1830]
Mean values, median values in parentheses and range in square brackets.
N is 80 and not 82 due to missing values for two patients regarding prior medical prophylaxis.
***P < 0.0001.
received prophylaxis. This difference was not statis-
tically signicant (P = 0.22) (Table 3).
Discussion
This study shows that patients with medication
overuse, who have no improvement in headache fre-
quency, by mere discontinuation of the offending
drug subsequently become responsive to therapeu-
tic intervention in the time period after drug
withdrawal.
Excluding patients who did not stay medication
free during withdrawal and subsequently excluding
patients who were administratively dismissed due
to failure to appear, resulted in a 50% exclusion rate.
Even then, our sample size is fairly large. As in all
open studies, bias is a possibility. The prospective
headache data, however, minimize the risk of bias
and comparisons between diagnostic groups are
unbiased. In addition, there is no social bias because
medical treatment is free for all residents in Den-
mark. All our patients had a long history of refrac-
tory headaches and had consulted one or several
neurologists before admission. The latter was due to
the referral criteria of DHC. It is therefore unlikely
that the observed improvement from the end of
withdrawal to dismissal is a simple placebo or time
effect. It is important to emphasize that generaliza-
tion of the results must be made with caution. Yet
there were no difference between enrolled and
excluded patients with regard to sex, primary head-
ache diagnoses or headache frequency, the excluded
were slightly younger and fewer overused specic
migraine drugs. Furthermore, few if any headache
clinics keep their patients completely drug free for
2 months and most allow prophylactic treatment
before 2 months.
Relative reduction in
headache frequency
from initial visit
After withdrawal At dismissal to dismissal, %
18 (16) [030] 14 (10) [030] 49 (59) [0100]***
24 (30) [630] 12 (7) [130] 56 (73) [097]***
21 (25) [030] 13 (9) [030] 53 (67) [0100]***
The age was slightly older and with less female
preponderance compared with other studies (1, 4,
1113). In a meta-analysis by Diener and Dahlf of
29 studies, 65% had migraine as primary headache,
27% TTH and 8% mixed migraine and TTH or other
headache diagnoses (8). The present study had a
much smaller proportion of pure migraine (10%), a
larger proportion of TTH (33%) and a much larger
proportion of mixed migraine and TTH (45%) and
OD (12%). This is probably due to our systematic
prospective use of diagnostic diaries where all head-
aches are recorded. As shown by Russell et al., epi-
sodic TTH is usually underdiagnosed and migraine
overdiagnosed in a diagnostic interview compared
with a diagnostic diary (14).
For all patients together the relative reduction in
headache frequency from the rst visit to dismissal
was 46%. The variation between the diagnostic
groups ranged between 30% for TTH and 64% for
pure migraine. Patients with mixed migraine and
TTH had a 55% reduction. These results are some-
what smaller than the 74% decrease in headache fre-
quency found by Bigal et al. 1 year after a successful
and maintained detoxication in patients with so-
called transformed migraine (1).
The most remarkable result in the present study
was the long-term treatment benet for the sub-
group of patients who had absolutely no initial
improvement in headache frequency following a 2-
month drug-free period. Our data show that one can
expect a signicant positive therapeutic response
after withdrawal for these patients, with a relative
reduction of 26% over a period averaging 249 days.
TTH patients had a signicantly poorer outcome
with a mean relative reduction of 13% compared
with 36% for mixed migraine and TTH and 32% for
OD. The largest improvement was observed in the
Blackwell Publishing Ltd Cephalalgia, 2006, 26, 11921198
 Discontinuation of medication overuse in headache patients
group with pure migraine (41%), yet this was not
signicant due to the small number of patients.
These ndings are in aggreement with other studies
which have reported a worse long-term prognosis
for TTH compared with migraine following drug
withdrawal (15, 16). We have previously shown that,
using headache frequency as the sole efcacy mea-
sure, the improvement following medication with-
drawal is less pronounced in TTH compared with
migraine (5) and have suggested that both intensity
and duration of the individual headache episode
should be included in the evaluation of treatment
outcome in TTH. The poorer long-term treatment
outcome in TTH is likely also to reect the lesser
efcacy and the small number of available prophy-
lactic drugs compared with migraine.
It is generally assumed that medication overuse
nullies the effect of prophylactic agents. The evi-
dence in the literature is, however, sparse (4). We
therefore wanted to relate the long-term treatment
outcome to a possible renewed effect of medical pro-
phylaxis. For this aim it is a problem that DHC is a
multidisciplinary headache clinic with standardized
procedures for the treatment of MOH involving doc-
tors, nurses, physiotherapists and psychologists (10).
As most of the patients receive combined therapy, it
was not possible to ascribe the overall outcome with
certainty to prophylactic drug treatment. We there-
fore looked at the 80 patients on medical prophylac-
tic treatment at dismissal. Of these, 43 patients had
a history of prior medical prophylaxis with no effect
on their headaches, while 37 had never tried pro-
phylactic agents. Comparing the treatment outcome
for these two groups, one would expect a poorer
outcome among the patients with a known non-
response to medical prophylaxis. However, we
found a highly signicant relative reduction in
headache frequency from rst visit to dismissal for
both groups and no signicant difference between
groups. The former non-responders had a 49%
reduction and the patients with no prior history of
prophylaxis reduced their frequency by 56%. This
strongly suggests a renewed effect of prophylaxis
after medication withdrawal and that medication
overuse nullies the effect of prophylactic agents.
Our data are important in relation to the diagnos-
tic criteria for MOH according to the International
Classication of Headache Disorders, 2nd edn. In
order to receive the MOH diagnosis, it is required
that patients must improve after drug withdrawal.
This was the case in only half of our patients. How-
ever, the other half who did not improve became
responsive to pharmacological and non-pharmaco-
logical therapeutic intervention. Thus, the vast
Blackwell Publishing Ltd Cephalalgia, 2006, 26, 11921198
1197
majority of patients had a positive result of drug
withdrawal, suggesting that the criteria for MOH in
ICHD-II are too strict.
In summary, this study shows that almost all
MOH patients benet from drug withdrawal, either
directly or by transformation from therapeutic non-
responsiveness to responsiveness.
Conict of interest
None declared.
Acknowledgements
The authors thank Mrs Hanne Andresen for technical assis-
tance during data collection. The study was supported by
grants from IMK Almene Fond. The funding source was not
involved in any stage of the study.
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