Clinical features, pathophysiology, and treatment of medication-overuse headache
Clinical features, pathophysiology, and treatment of medication-overuse headache Medication-overuse headache (MOH) is a chronic headache disorder deﬁ ned by the International Headache Society Lancet Neurol 2010; 9: 391–401 as a headache induced by the overuse of analgesics, triptans, or other acute headache compounds. The population- See In Context page 349 based prevalence of MOH is 0·7% to 1·7%. Most patients with MOH have migraine as their primary headache and Department of Neurology, overuse triptans or simple analgesics. The pathophysiology of MOH is still unknown. As well as psychological University of Münster, Germany (S Evers MD, mechanisms such as operant conditioning, changes in endocrinological homoeostasis and neurophysiological M Marziniak MD) changes have been observed in patients with MOH. Recently, a genetic susceptibility has been postulated. In most Correspondence to: cases, treatment of MOH consists of abrupt withdrawal therapy and then initiation of an appropriate preventive drug Stefan Evers, Department of therapy. There is no clear evidence on which method of withdrawal therapy is the most eﬃ cacious. Withdrawal Neurology, University of symptoms can be treated with steroids; however, not all data support this concept. As MOH can severely aﬀ ect the Münster, Albert- quality of life of patients, it needs to be recognised early to enable appropriate treatment to be initiated.
48129 Münster, Germany firstname.lastname@example.org Introduction
although the various approaches need to be more
Medication-overuse headache (MOH) is a chronic disorder
that results from the overuse of analgesics, triptans, or other acute headache compounds. This disorder can have
Epidemiological and socioeconomic aspects
a severe eﬀ ect on the quality of life of patients and can The prevalence rates of MOH are similar across diﬀ erent have a high economic burden on society. It was not until countries. The 6-month prevalence of MOH in Germany 1951 that chronic headache in patients with migraine or was 1·0% with a higher preponderance in women (74%) tension-type headache who were overusing ergotamine than men (26%) and a mean age of 53 years.6 In other compounds was reported and that withdrawal of these countries, the prevalence rates were similar (average substances led to fewer occurrences of this chronic 1·1%), although diﬀ erent methods of diagnosis and headache.1 In a second study, the authors conﬁ rmed this diﬀ erent prevalence periods were used (table 1).6–11 Among ﬁ nding and extended it to the overuse of combinations patients aged older than 65 years, the prevalence rates with barbiturates and caﬀ eine.2 In these ﬁ rst studies, ranged between 1·0% in Taiwan12 and 1·7% in Italy.13 MOH was mainly associated with the overuse of
The incidence of MOH has not been studied in speciﬁ c
ergotamine derivatives and was therefore ﬁ rst called population-based studies. In a study on episodic ergotamine headache. In the 1980s, studies on MOH migraineurs (n=532), the 1-year incidence of chronic caused by simple analgesics and by combined analgesics headache was 14%, with a higher risk for patients who were published, and MOH was recognised as a general had a higher headache frequency at baseline and for problem of treatment for all headache subtypes.3–5
patients taking greater amounts of analgesics.14
As the number of patients presenting with this disorder
Among patients in headache clinics or centres of
to headache centres is growing, partly owing to the use of
tertiary care, patients with MOH form the largest group,
triptans, MOH has become one of the major challenges together with migraine and tension-type headache, in headache treatment. It is important to diﬀ erentiate including subtypes of chronic daily headache. Up to 30% MOH from other types of chronic daily headache. The of patients in such centres in Europe, and even more concept of chronic daily headache has been developed in
than 50% in the USA, present with MOH.15–17 In India,
recent years, but it is also widely debated and still awaits only 3·1% of the patients in a headache clinic fulﬁ l the suﬃ
cient classiﬁ cation. Thus, MOH needs to be clearly criteria for MOH, with 57% of them overusing ergotamine
deﬁ ned as a separate subtype within the concept of derivatives.18 chronic daily headache and with speciﬁ c treatment
Patients with MOH are more likely to have a low
requirements. In recent years, MOH has been income and a lower educational level than the general investigated in both clinical and experimental studies. population.10,19,20 Data from two German studies have also These studies have shown that MOH has a distinct indicated a higher prevalence of MOH in immigrants clinical picture and a clear biological basis.
from southern or eastern European countries compared
In this Review, we evaluate recent data on the clinical with native Germans.10,21 In a study of a speciﬁ c working
c treatment recommendations, and population (n=471), the 1-year prevalence of MOH was
pathophysiology of this disorder. In particular, the 16·5% in ﬁ
deﬁ nition of MOH in contrast to other types of chronic Germany, but only 1·5% in second-generation Turkish daily headache is explained and diﬀ erentiated through-
immigrants and 1·1% in native Germans.21 This
out the text. The recommendations on the treatment of diﬀ erence was because the ﬁ rst-generation Turkish MOH are based on a review of the best available evidence,
immigrants did not seek medical help. Low educational
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patients from a prospective point of view (ie, at the time
Prevalence Female sex Mean age
of consultation) and not retrospectively (ie, after
The primary headache disorder leading to MOH is
migraine in most cases.9,15,28 Patients with MOH tend to
have their ﬁ rst migraine attack earlier than patients with
episodic migraine.29 This type of chronic headache (ie,
more than 15 days per month) generally starts earlier in life than do other types of chronic headache.9 There is a
Table 1: Prevalence rates and demographic features of
preponderance of MOH in women (up to 95%) than in
medication-overuse headache in population-based studies
Risk factors for the development of MOH have been
level, low occupational status, and low income (the latter
examined in cohort studies but exact odds ratio or relative
for only men) were associated with an increased risk for risk calculations are not available. In general, compared MOH.22
with patients with episodic migraine, patients with
The general quality of life of patients with MOH is migraine and MOH are more likely to be of female sex,
poorer than for patients with episodic headache, as have lower levels of educational attainment, be married, measured by the General Health Questionnaire-28.20
be unemployed, have migraine remission during
Additionally, results from the quality of life short-form 36 pregnancy, be menopausal, have constipation, not use (SF-36) health survey revealed a decreased score in all oral contraceptives, have higher use of health-care health-related domains for patients with MOH compared resources (particularly neuroimaging, hospitalisation, with healthy individuals, with the highest diﬀ erences for and other headache centres), and be on polypharmacy bodily pain and physical activity.9 The migraine-speciﬁ c (particularly sedative-hypnotics, anti-hypertensives).29and chronic headache-speciﬁ c migraine disability
The mean number of monthly drug units taken by
assessment (MIDAS) scores are about threefold higher in
patients with MOH is between 10 and 180 with an average
patients with MOH than in patients with episodic of 50.9 However, it is recommended and agreed by experts migraine, and are similar to those of patients with other not to count the number of drug units per month but the types of chronic daily headache.15
number of days per month with intake of an acute drug.
Interestingly, MOH mainly occurs in patients with a
primary headache disorder and this has been clearly
Classiﬁ cation criteria
shown for migraine and tension-type headache. Patients
The ﬁ rst classiﬁ cation and diagnostic criteria were with cluster headaches can also fulﬁ l the criteria for published in 1988 by the International Headache Society
MOH.30,31 However, most of these patients have migraine
cation termed the as a comorbid headache or migraine in their family
disorder drug-induced headache and diﬀ erentiated history, and many patients with cluster headache take between only ergotamine-induced and analgesic abuse analgesics, ergotamine derivatives, or triptans on a daily headaches.
basis without having MOH. Exceptions to the rule that
In 2004, the second edition of the IHS headache only primary headaches can lead to MOH have been
classiﬁ cation (the ICHD-II) was published with a new published for post-traumatic headache32 and for some systematic approach to MOH.24 However, it was soon other secondary headache disorders.33–35 obvious that some subtypes were missing and that
Patients with other pain disorders such as rheumatic
headache features of MOH cannot be deﬁ ned in general.
diseases and no headache disorder do not develop chronic
Therefore, a new revision of these diagnostic criteria, headache de novo when taking analgesics or similar shown in panel 1, was published in 2005.25 These criteria
centrally acting drugs for their pain condition.36–38 However,
are still valid today, although a further revision has been if these patients have a susceptibility to migraine, they can published in 2006 as so-called appendix criteria.26 This also develop chronic daily headache.37,38 Another interesting second revision to the MOH criteria of the ICHD-II ﬁ nding was a report of a patient with both typical migraine classiﬁ cation (panel 2) is mainly intended for research and migraine without headache but with abdominal pain purposes and scientiﬁ c evaluation and can be used in who showed an increased frequency for both symptoms clinical trials but not for routine clinical diagnosis.26 Use with the overuse of analgesics, which resolved after of the research criteria led to identiﬁ cation of a higher discontinuation of analgesic intake.39 number of patients with MOH, whereas the current
The adherence of the individual patient to his or her
main criteria led to identiﬁ cation of a substantial number
speciﬁ c pain medication (ie, the level of dependence on a
of patients with probable, instead of clear, MOH.27 An speciﬁ c substance and the strictness of intake of that advantage of the research criteria is that they include substance) is greater for patients with MOH than for
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patients with daily rheumatic pain; the closest adherence was for the overuse of triptans and combined analgesics.40
Panel 1: Current diagnostic criteria for medication-overuse headache, as proposed by
Therefore, triptans and combined analgesics have the
the International Headache Society25 Medication-overuse headache (8.2) Diagnostic criteria Comorbidities
A Headache* present on ≥15 days per month fulﬁ lling criteria C and D
Comorbidities have become an important factor in the
B Regular overuse† for ≥3 months of one or more drugs that can be taken for acute or
epidemiological research of headache disorders.
Comorbidities are particularly important for MOH
C Headache has developed or markedly worsened during medication overuse
because this headache type has, in general, more
D Headache resolves or reverts to its previous pattern within 2 months after
comorbid disorders than do episodic headache types
(except allergies and thyroid function disorders, which are more common in episodic headaches).29
Subtypes of medication-overuse headache
The comorbidities of the underlying headache disorder
Ergotamine-overuse headache (8.2.1)
with other diseases and the speciﬁ c comorbidities of
Ergotamine intake on ≥10 days per month on a regular basis for >3 months
MOH need to be diﬀ erentiated. Subclinical obsessive-
compulsive disorder as measured by the Yale-Brown
Triptan intake (any formulation) on ≥10 days per month on a regular basis for >3 months
scale is more common in patients with MOH than in
Analgesic-overuse headache (8.2.3)
patients with episodic or chronic migraine.41 Additionally,
Intake of simple analgesics on ≥15 days per month on a regular basis for >3 months
anxiety and mood disorders are more frequent in patients with MOH;41 this might be due to the known comorbidity
of migraine and diﬀ erent psychiatric disorders. However,
Opioid intake on ≥10 days per month on a regular basis for >3 months
compared with patients with migraine, there is an
Combination analgesic-overuse headache (8.2.5)
increased risk of mood disorders, anxiety, and disorders
Intake of combination analgesic medications¶ on ≥10 days per month on a regular basis
associated with the use of psychoactive substances other
than analgesics in patients with MOH. This risk was
Medication-overuse headache attributed to the combination of acute medications (8.2.6)
cantly more frequent even before the Intake of any combination of ergotamine, triptans, analgesics, and/or opioids on ≥10 days
transformation from migraine into MOH than after
per month on a regular basis for >3 months without overuse of any single class alone||
MOH had developed.42 The comorbidity with psychiatric disorders is not restricted to only migraine as the pre-
Headache attributed to other medication overuse (8.2.7)
existing primary headache type, but also occurs in
Regular overuse** for >3 months of a medication other than those described above
Probable medication-overuse headache (8.2.8)
According to criteria in the fourth edition of the
fulﬁ lling criteria A, C, and D for 8.2
diagnostic and statistical manual of mental disorders
fulﬁ lling criterion B for any one of the subforms 8.2.1 to 8.2.7
(DSM-IV), the overuse of analgesics and acute migraine
drugs fulﬁ ls the criteria of substance abuse disorder in
1 Overused medication has not yet been withdrawn
two-thirds of all patients with MOH.44 Thus, a positive
2 Medication overuse has ceased within the last 2 months but headache has not yet
result in the severity of dependence scale was associated
resolved or reverted to its previous pattern
with medication overuse in patients with chronic headache.45 Pathological abuse of nicotine or caﬀ eine has
*The headache associated with medication overuse is variable and often has a peculiar pattern with characteristics shifting, even within the same day, from migraine-like to tension-type headache. †Overuse is deﬁ ned in terms of duration and
not been found in patients with MOH.10 However, there
treatment days per week. What is crucial is that treatment occurs both frequently and regularly (ie, on 2 or more days each
is a high prevalence of smokers and individuals with a
week). Bunching of treatment days with long periods without medication intake, practised by some patients, is much less likely to cause medication-overuse headache and does not fulﬁ l criterion B. ‡Medication-overuse headache can occur in patients who
body-mass index of more than 30 among patients with
are headache-prone when acute headache medications are taken for other indications. §A period of 2 months after cessation of
MOH.6 The presence of these features might be indicative
overuse is stipulated in which improvement (resolution of headache or reversion to its previous pattern) must occur if the
of frontal lobe dysfunction in patients with MOH.
diagnosis is to be deﬁ nite. Before cessation, or pending improvement within 2 months after cessation, the diagnosis 8.2.8 (Probable medication-overuse headache) should be applied. If such improvement does not then occur within 2 months, this
Sleeping problems are also more common in patients
diagnosis must be discarded. ¶Combinations typically implicated are those containing simple analgesics combined with
with MOH than in patients with episodic headache.10
opioids, butalbital, and/or caﬀ eine. ||The speciﬁ c subform(s) 8.2.1–8.2.5 should be diagnosed if criterion B is fulﬁ lled in respect
Whether this association is due to the medication overuse
of any one or more single class(es) of these medications. **The deﬁ nition of overuse in terms of treatment days per week is likely to vary with the nature of the medication.
itself or to the chronic headache is not yet known.
Types of medications overused
diﬀ erent drugs and whether the risks are diﬀ erent.
In principle, all acute drugs for the treatment of headache
Furthermore, whether simple analgesics and dihydro-
could cause MOH (ie, ergotamine derivatives, ergotamine are able to induce MOH is still debated.28 barbiturates, triptans, simple and combined analgesics,
Until the beginning of the 1980s, only ergotamine
opioids, benzodiazepines, and possibly also caﬀ eine). derivatives were thought to cause MOH, then analgesics, However, there is debate about whether there are particularly combined analgesics, were identiﬁ ed as a diﬀ erences in the clinical features of MOH induced by cause of MOH. The ﬁ rst case reports on MOH caused by
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smaller amounts of ergotamine derivatives or triptans
Panel 2: Appendix criteria for medication-overuse headache (for research and clinical trial purposes only)26
The headache features of MOH caused by ergotamine
derivatives are more severe than those caused by
Medication-overuse headache (appendix 8.2)
triptans.51,54 The combination of triptan and analgesic
overuse causes higher headache frequency and intensity
A Headache present on ≥15 days per month
and more accompanying symptoms than the overuse of
B Regular overuse for >3 months of one or more
triptans alone.55 Patients who overuse ergotamine and
acute/symptomatic treatment drugs as deﬁ ned under
analgesics typically have a daily tension-type-like
headache, whereas patients with triptan-induced MOH
1 Ergotamine, triptans, opioids, or combination
are more likely to describe a (daily) migraine-like
analgesic medications on ≥10 days per month on a
headache or an increase in migraine frequency.54 In a
population-based prospective study from the USA, only
intake of barbiturates or opioids was signiﬁ cantly
triptans, analgesics, or opioids on ≥15 days per month
associated with the development of chronic headache,
on a regular basis for >3 months without overuse of
As up to 90% of all patients with MOH take more than
C Headache has developed or markedly worsened during
one speciﬁ c drug for acute attack treatment, it is not
possible to exactly diﬀ erentiate between the features of diﬀ erent MOH subtypes according to the drug overused.
triptans were published in 1994.46–48 This ﬁ nding was then replicated by other groups in larger samples49–51 until this Complications of MOH eﬀ ect of triptans was generally accepted. Nowadays, at MOH can lead to several somatic complications, most of least in some high-income countries, triptans are the which are caused by the side-eﬀ ects of the overused drugs. most frequent drug taken by patients who develop MOH.52
Here, we present only the speciﬁ c sequelae of drug
Previously, this was the case for ergotamine derivatives overuse in patients with MOH and not the side-eﬀ ects or and then, for a short period, for barbiturates until the adverse events of these drugs. Most of the problems in latter drugs were removed from the market as migraine-
patients with MOH have been described for ergotamine
relieving drugs (at least in European countries). However,
overuse. These side-eﬀ ects include sensory neuropathy,56
in India, ergotamine is still the most common drug that slowing of central cognitive processing,57,58 and decreased leads to MOH.18 The new class of calcitonin gene-related distensibility or changes in the arterial vessel wall peptide antagonists in the acute treatment of migraine structure of the brain-supplying arteries.59,60 Additionally, attacks has been suggested to not cause MOH. However, impaired psychological functioning, described as distress, when looking at the history of this disorder and the is associated with ergotamine overuse.61 Other types of mechanisms involved in its pathophysiology, it is unlikely
drug overuse can also cause changes in the nervous
that these substances should not also cause MOH.
system. Latencies of peripheral autonomic potentials
The range of compounds taken (not necessarily overused)
were increased in patients with diﬀ erent types of MOH.62
by patients with MOH varies widely between the time There is no evidence to date that any analgesics without periods of the studies and between diﬀ erent regions. In a phenacetin can induce nephropathy.63–65 Only phenacetin Spanish study, for example, of 4855 people aged 14 years or has clearly caused analgesic nephropathy. over, most patients had taken paracetamol (54%), and others had taken caﬀ eine (49%), ergotamine (38%), propyphenazone
(35%), aspirin (18%), codeine (13%), and triptans (3%).9
The somatic pathophysiology and the psychological
There is still no epidemiological or experimental proof mechanisms of MOH are almost completely unknown.
that combined drugs (in particular those containing It is only possible to describe some of the mechanisms caﬀ eine) are more likely to cause MOH than single that are associated with MOH or that predispose patients substances.53 Combined drugs are commonly available to this disorder. over the counter and prescribed frequently, which is reﬂ ected in the high representation of these substances Neurophysiology among all patients with MOH. Triptans and ergotamine In Doppler ultrasound studies, the mean blood ﬂ ow derivatives are more likely to induce MOH than are velocity was increased in patients with ergotamine- simple analgesics.28 The time until development of MOH
overuse headache compared with patients with simple
analgesic-overuse headache and healthy control
were found to be highest for simple analgesics than for individuals.66 However, this is probably a pharmacological all other analgesics.51,54 However, there are contradictory eﬀ ect of ergotamine. results on whether ergotamine derivatives or triptans
The sympathetic skin response has also been examined
need a shorter duration to induce MOH and whether in patients with MOH. In one study, increased latencies
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in patients with MOH were found.62 This ﬁ nding was stimulating hormone responses, and adrenocorticotropic conﬁ rmed in another study, albeit only for patients with hormone and cortisol concentrations were increased.76MOH and psychiatric comorbidity.67
In patients with MOH, 5-HT receptors were
Experimental electrical peripheral pain stimulation upregulated and more dense on platelet membranes
causes central sensitisation in patients with MOH.68
compared with healthy controls.77,78 Additionally, the
Subsequently, advanced methods such as pain-related platelet content of 5-HT was low, suggesting that cortical potentials have been used to detect facilitation of
suppression of 5-HT uptake induced by medication
supraspinal pain processing in patients with MOH, overuse might be one mechanism that underlies MOH.79 which disappeared after withdrawal therapy. This This ﬁ nding was conﬁ rmed in other studies that showed facilitation was observed with trigeminal and somatic lower endocannabinoid and 5-HT platelet concentrations pain processing, but not with the nociceptive blink reﬂ ex, in patients with MOH80 and increased activity of the which indicates the involvement of spinal pain-processing
serotonin transporter mechanisms in these patients
Other studies of the plasma con centrations of diﬀ erent
hormones and neurotransmitters in MOH have shown
A hereditary susceptibility to MOH has been proposed decreased β-endorphin and opioid concentrations,82 on the basis of epidemiological evidence. The risk of increased norepinephrine turnover,83 and increased MOH is increased threefold if there is a family history inositol phosphate production in platelets.84 of MOH or other substance abuse such as drug or alcohol abuse.29,70 The risk of developing drug overuse or Functional imaging substance abuse is increased fourfold if another family In a study that used ﬂ uorine-18-labelled-ﬂ uoro deoxy- member has had MOH.70
glucose (18-FDG) PET, patients with MOH were
Recently, molecular genetic factors have also become a investigated before and 3 weeks after withdrawal
focus in research on MOH pathophysiology. The therapy and were compared with healthy control Val66Met polymorphism in brain-derived neurotrophic individuals.85 After withdrawal therapy, the earlier factor, which is related to behavioural disorders and hypometabolism of the bilateral thalamus, anterior substance abuse, is associated with increased analgesic cingulate gyrus, insula/ventral striatum, and right drug consumption in patients with MOH.71 This ﬁ nding inferior parietal lobe normalised in patients with MOH. suggests that MOH is, at least in part, a substance abuse
However, the hypometabolism of the orbitofrontal
disorder rather than just a complication of the underlying
cortex did not change. This ﬁ nding is also known from
idiopathic headache disorder. In another study, allele 10 other types of drug dependency and again suggests that of the dopamine transporter gene (SLC6A3; also known MOH might be a consequence of a susceptibility to as DAT1) was signiﬁ cantly under-represented in patients substance abuse. with MOH compared with patients with episodic
Analysis of grey matter revealed a signiﬁ cant decrease
erent genotypic and allelic in brain structures involved in pain processing only for
distributions of the known polymorphisms of several patients with chronic tension-type headache but not for 5-HT receptor genes do not seem to have a role in the patients with MOH. The patients with MOH had only a genetic susceptibility to MOH.73
non-signiﬁ cant decrease in grey matter in the left
All these studies on molecular genetics in MOH were orbitofrontal cortex and the right midbrain.86
done with small sample sizes and need to be reproduced in diﬀ erent ethnic groups. Therefore, the results must be
regarded as preliminary at this stage.
In the early years when MOH was ﬁ rst recognised as a distinct disorder, psychological research focused on
Endocrine and neurotransmitter function
learning and behaviour theory. According to operant
Increased concentrations of orexin A and corticotrophin-
conditioning theory, in MOH, drug intake was described
releasing factor have been detected in the CSF of patients
as a negative reinforcement with regard to the reduction
with MOH and, to a lesser extent, in patients with chronic
of pain and a positive reinforcement with regard to the
migraine.74 There was also a positive correlation between
these increased concentrations and the amount of drug patients with MOH were found to dislike analgesics but intake. The CSF concentration of glutamate was believed that they could not cope without them. To signiﬁ cantly lower in patients with MOH who overused overcome this situation, counselling of the patients triptans compared with patients with migraine who did together with prophylactic drug intake was suggested.87 not overuse triptans, although concentrations were
It has also been assumed that MOH is a subtype of
signiﬁ cantly higher compared with healthy control drug addiction as most of the drugs taken by patients individuals.75
who develop this disorder contain substances with
In endocrinological stimulation tests, patients with psycho tropic eﬀ ects such as barbiturates, opioids, and
MOH had reduced growth hormone and thyroid caﬀ eine. However, there is no evidence for true addiction
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to triptans or to simple analgesics. Therefore, this cological therapy improves headache in MOH, and the mechanism cannot fully explain the development of combination of both has had better outcomes than has MOH. Additionally, the personality proﬁ le of patients pharmacological therapy alone for reducing long-term with MOH does not diﬀ
er from healthy control relapses and improving quality of life in a non-
individuals with regard to addiction potential and randomised study94 and in a randomised95 3-year follow-addiction admission as measured by the Minnesota up study. In another study,96 120 patients with multiphasic personality inventory.88
uncomplicated MOH were treated with three diﬀ erent
A more diﬀ erential approach is now suggested to explain
modalities: only strong advice to withdraw overused
MOH from a psychological point of view. As well as medication; a standard outpatient detoxiﬁ cation somatic factors such as a genetic susceptibility,70 fear and programme (rapid withdrawal from overused medication, catastrophisation of headache pain are important aspects oral prednisolone for 8 days, and personalised of the transformation from episodic headache with single
prophylactive drugs); or an inpatient programme (rapid
drug intake to chronic headache with medication overuse.
withdrawal from overused medication, oral prednisolone
Additionally, comorbidity with depression is recognised to
for 8 days, treatment with personalised prophylactive
be an important factor, although aﬀ ective symptoms do drugs, parenteral ﬂ uid and antiemetics, and close not seem to predict dependence on analgesics or even observation for 8 days). The numbers of patients who opioids in headache treatment.47
achieved successful withdrawal and had reduced headache frequency were not diﬀ erent between groups Withdrawal treatment
during the follow-up period of 60 days after withdrawal.96
Headache experts agree that withdrawal therapy should
A direct comparison between inpatient withdrawal and
be oﬀ ered to patients with MOH, although the evidence outpatient withdrawal treatment showed that both base for this approach is limited. The goal of this methods led to a signiﬁ cant decrease in headache days treatment is not only to detoxify the patients and stop the
per month after 12 months and a reduction in migraine
chronic headache but also to improve responsiveness to disability scores without superiority of one method.97 acute or prophylactic drugs.89
Because the outpatient withdrawal approach is less expensive than the inpatient withdrawal approach, and is
as successful in a motivated group of patients, it is the
The procedures for withdrawal in patients with MOH preferred method in many cases. However, advantages of vary substantially, and no study has compared abrupt inpatient withdrawal are that it enables the close withdrawal treatment with tapered withdrawal in monitoring of medication intake and clinical state, prospective randomised trials. Most headache specialists immediate treatment of withdrawal symptoms, and are in favour of abrupt discontinuation of pain medication
treatment with intravenous drugs. Overuse of opioids,
because this is thought to be associated with fast resolution
barbiturates, or benzodiazepines, psychological problems,
of the drug-induced pain-coping behaviour.90 However, severe medical comorbidities, severe withdrawal tapered withdrawal might be recommended for opioids, symptoms (eg, vomiting and status migrainous), or barbiturates and, in particular, benzodiazepines to reduce
previous medication withdrawal failure are reasons for
withdrawal symptoms. The main withdrawal symptoms inpatient treatment according to expert consensus or are worsening of the headache, nausea, vomiting, arterial
national guidelines.98–100 However, this recommendation
hypotension, tachycardia, sleep disturbances, restlessness,
is not supported by randomised prospective trials.
anxiety, and nervousness. These symptoms generally last
An unanswered question is whether prophylactic
between 2 and 10 days, but can persist for up to 4 weeks. treatment should be started before, during, or after The withdrawal headache seems to be shorter in patients
withdrawal. A recent prospective, multicentre study
who have taken triptans (mean 4·1 days) than in patients investigated three treatment groups: personalised who have taken ergotamine (mean 6·7 days) or NSAIDs preventive medication from day 1 (n=17); abrupt (mean 9·5 days).91
withdrawal plus rescue medication (n=20); and no
The outcome of withdrawal therapy in patients with preventive medication plus no advice to stop overused
MOH followed up by a neurologist compared with a drugs (n=19).101 The primary endpoint, change in primary care physician did not diﬀ er signiﬁ cantly for headache days, did not diﬀ er signiﬁ cantly between all calculated mean days of headache and improvement of three groups. The more pronounced reduction in the headache.92 Therefore, these patients can be followed up headache index in the ﬁ rst group compared with the by primary care physicians, neurologists, or pain second group might suggest an advantage for a specialists.
personalised preventive medication without abrupt
Non-pharmacological approaches for treatment of withdrawal. Important drawbacks of this study are the
MOH are important tools to help patients to learn to small numbers of patients in each group and a restructure their cognitive approach to pain and to learn spontaneous reduction of drug intake in the control to tolerate discomfort and emotional distress.93 Combined
group. In summary, further larger, prospective trials are
short-term psychodynamic psychotherapy and pharma-
necessary to answer these urgent questions.
www.thelancet.com/neurology Vol 9 April 2010 Treatment of withdrawal headache
The relapse rates from diﬀ erent studies3,106–123 are
Studies of speciﬁ c preventive therapies for MOH are presented in table 2. These rates do not diﬀ er signiﬁ cantly not available. Therefore, the choice of preventive drug when a short or a long observation period is used. In one in MOH should be based on the primary headache study, for example, the relapse rate was 23% after (migraine vs tension-type headache), the possible side-
2 months and after 1 year in the same sample;122 in
eﬀ ects of the drugs, the comorbidities, and the patient’s
another example, the relapse rate was 41% after 1 year
preference and previous therapeutic experiences. and 44% after 4 years.118 Results from several open-label trials indicate positive
In an Italian study on diﬀ erent methods of withdrawal
eﬀ ects of diﬀ erent substances, such as valproic acid and
therapy, a long duration of migraine before medication
topiramate, in the prophylactic treatment of chronic overuse, a high frequency of migraine after withdrawal daily headache with excessive medication intake. In a therapy, and a high number of previous preventive double-blinded trial in patients with chronic migraine treatments were associated with an increased risk for and MOH, there was a signiﬁ cant reduction in the relapse of MOH.120 In another study, predictors of relapse mean number of migraine days per month in patients were male sex, intake of combination analgesics after treated with topiramate (target dose 100 mg per day; withdrawal therapy, and taking the causative medication allowed range 50–200 mg) in comparison to placebo again after withdrawal therapy.116 Recently, use of codeine-(–3·5±6·3 vs –0·2±4·7; p<0·05). However, side-eﬀ ects containing drugs, low self-reported sleep quality, and were reported by 75% of the patients in the topiramate high self-reported bodily pain as measured by the SF-36 group compared with 37% in the placebo group.102 The questionnaire were predictors of a poor outcome.121 In a reduction in headache occurrence was not large enough
multivariate analysis, the frequency of primary headache
to indicate a change from chronic headache to an disorder, ergotamine overuse, and disability score for episodic form.
chronic headache estimated by MIDAS were indicated to
As most drugs used for the treatment of withdrawal be independent predictors of treatment eﬃ
headache can cause MOH themselves, corticosteroids follow-up.123 In some studies, the prognosis was better for are an appealing option. The only placebo-controlled, patients who had migraine as the underlying primary randomised, double-blind study that has investigated headache disorder than for patients who had tension-treatment with oral prednisolone during the ﬁ rst 6 days type headache and for ergotamine or triptan withdrawal after medication withdrawal revealed no eﬀ ect of the than for analgesic withdrawal.118,124 corticosteroid on a combined primary endpoint. Of 97 patients, 49 received prednisolone (60 mg on days 1
Relapse rate Follow-up Type of withdrawal therapy
and 2, 40 mg on days 3 and 4, and 20 mg on days 5 and 6)
and 48 patients were on placebo.103 Conversely, in an
open-label trial that involved 400 patients with chronic
daily headache and who had medication overuse,
treatment with 60 mg prednisone for 2 days that was
tapered down by 20 mg every other day eﬀ ectively reduced
rebound headache and withdrawal symptoms.104 In a
small proof-of concept study in which nine patients with
MOH received either placebo or 100 mg prednisone for
5 days,105 the duration of withdrawal headache was
signiﬁ cantly lower in the prednisone group compared
with the placebo group. Taken together, these results
suggest that corticosteroids might be eﬀ ective for
treatment of withdrawal symptoms in patients with
MOH, but further high-quality, placebo-controlled trials
Prognosis after withdrawal therapy
The prognosis of MOH depends almost solely on use of
an appropriate withdrawal therapy. However, the types of
withdrawal therapy vary widely, although the relapse rate
seems to be about 30% after 1 year, regardless of whether
inpatient, outpatient, or advice-alone treatment was used.
This rate is low compared with the rates for other
addictive disorders. However, as MOH is an avoidable disorder, this relapse rate should be even lower with
Table 2: Relapse rates after diﬀ erent types of withdrawal therapy in studies of medication-overuse headache
www.thelancet.com/neurology Vol 9 April 2010
ﬁ ndings in prospective studies (ie, primary prevention
Search strategy and selection criteria
studies). The problem with such studies is that they would need a long observation period of about 10 years.
References for this Review were identiﬁ ed through searches
MOH also emphasises the need for eﬀ ective preventive
of PubMed from 1966 to December, 2009, with the search
strategies such as early initiation of prophylactic headache
terms “medication overuse headache” and “drug-induced
drugs and behavioural therapy. There is still no evidence
headache”. All papers that used the former IHS deﬁ nition
on which regimen is the most appropriate for patients
from 1988 or the actual deﬁ nition including the term
with MOH. Prospective controlled studies with diﬀ erent
“probable MOH” were considered as research papers on MOH.
types of preventive medication are needed to identify the
Articles were also identiﬁ ed through searches of the authors’
best way to combine withdrawal treatment with drug
own ﬁ les. Only papers published in English or German were
reviewed. Papers that used diﬀ erent deﬁ nitions of chronic
psychotherapeutic interventions is still unclear.
daily headache with or without medication overuse were not
Prospective treatment trials should therefore also
considered if they did not follow the IHS criteria.
consider a comparison of drug and non-drug treatment (and the combination of both). Finally, increased public
MOH in children and adolescents
awareness about the need to restrict intake of acute
Data from several studies indicate that MOH can also headache medication should also contribute to primary occur in children and adolescents.57,125–129 A population-
based epidemiological study in Taiwan detected a 1-year Contributors prevalence of 0·3% in adolescents who overused Both authors reviewed the databases for relevant papers. MM wrote the analgesics available over the counter (mainly combined sections on treatment and SE wrote the remaining sections. The ﬁ nal analgesics);125 a similar ﬁ
gure of 0·5% with a paper was carefully reviewed by both authors.
preponderance in females of 4:1 was found in Norwegian
Conﬂ icts of interest SE has received unrestricted research grants and honoraria from Addex,
adolescents.130 This pattern has also been conﬁ rmed in AGA Medical, Allergan, Berlin-Chemie, Boehringer, CoLucid, Eisai,
other studies.126 Children and adolescents mainly overuse
GlaxoSmithKline, Janssen-Cilag, Merck, Novartis, Pﬁ zer,
analgesics,127 caﬀ eine-containing analgesics,129 and, only Reckitt-Benckiser, and UCB. MM has received unrestricted research rarely, ergotamine derivatives.57
grants and honoraria from Allergan, MSD, Pﬁ zer, Solvay, Teva, Bayer Schering Pharma, Biogen Idec, Sanoﬁ -Aventis, and Merck Serono.
Female children and adolescents with MOH report
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11 July 2008 Funding of levetiracetam approved PHARMAC’s Board has approved the funding of the Keppra brand of the antiepilepsy agent levetiracetam for selected patients via a special access process, from 1 August 2008. The Board also approved funding of Rex Medical Ltd’s brand of levetiracetam (Levetiracetam-Rex) for all patients as soon as possible following Medsafe registration.
Gesamtverzeichnis der wissenschaftlichen Publikationen Wissenschaftliche Publikationen Originalarbeiten: 1. Holographic interferometry of excimer laser ablated bovine eyes – First results. W. Förster, T. Stupp , H. Kasprzak; Ophthalmologica (2003);217:62- 2. Influence of medical and natural mydriasis on higher order aberrations of the eye. W. Förster, T. Stupp , J. Fiedler,