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.
Clinical features, pathophysiology, and treatment of medication-overuse headacheClinical features, pathophysiology, and treatment of
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
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 www.thelancet.com/neurology Vol 9 April 2010
patients from a prospective point of view (ie, at the time Prevalence
Female sex Mean age
of consultation) and not retrospectively (ie, after Syndromatic features
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 Clinical picture
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 www.thelancet.com/neurology Vol 9 April 2010
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)
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 www.thelancet.com/neurology Vol 9 April 2010
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 Pathophysiology
(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 www.thelancet.com/neurology Vol 9 April 2010
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 Genetic factors
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 Psychological mechanisms
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 www.thelancet.com/neurology Vol 9 April 2010
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
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 Withdrawal procedure
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
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
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 anxiety and depression signiﬁ cantly more often than do References
Peters GA, Horton BT. Headache: with special reference to the age-matched healthy control individuals, and parents of excessive use of ergotamine preparations and withdrawal eﬀ ects. children and adolescents with MOH report somatisation Mayo Clin Proc 1951; 26: 153–61.
signiﬁ cantly more often than do parents of children 2 Horton BT, Peters GA. Clinical manifestations of excessive use of ergotamine preparations and management of withdrawal eﬀ ect: without MOH.126 However, in a population-based study of report of 52 cases. Headache 1963; 3: 214–26.
adolescents, the higher risk for anxiety, depression, and 3 Isler H. Migraine treatment as a cause of chronic migraine. suicide was linked to chronic daily headache in general In: Rose CF, ed. Advances in migraine research. New York: Raven Press, 1982: 159–64.
Wörz R. Eﬀ ects and risks of psychotropic and analgesic combinations. Am J Med 1983; 139–40.
However, only few data are available on the best treatment Dichgans J, Diener HC, Gerber WD, Verspohl EJ, Kukiolka H, for this age-group. At 1 month after withdrawal therapy, Kluck M. Analgetika-induzierter Dauerkopfschmerz.
Dtsch Med Wochenschr 1984; 109: 369–73.
about 53% of all children had a reduction in headache 6 Straube A, Pfaﬀ enrath V, Ladwig KH, et al. Prevalence of chronic frequency of more than 90% regardless of whether they migraine and medication overuse headache in Germany-the were on preventive medication or not; the only predictor German DMKG headache study. Cephalalgia 2009; published online June 1. DOI:10.1111/j.1468-2982.2009.01906.x.
for a poor outcome after withdrawal therapy was a 7 Lu SR, Fuh JL, Chen WT, Juang KD, Wang SJ. Chronic daily duration of MOH of longer than 2 years.127 headache in Taipei, Taiwan: prevalence, follow-up and outcome
predictors. Cephalalgia 2001; 21: 980–86.
Zwart JA, Dyb G, Hagen K, Svebak S, Stovner LJ, Holmen J. Analgesic overuse among subjects with headache, neck, and MOH is a common and disabling headache disorder that low-back pain. Neurology 2004; 62: 1540–44.
should be familiar to every neurologist and patients with Colás R, Muñoz P, Temprano R, Gómez C, Pascual J. Chronic daily MOH should be referred to appropriate centres for headache with analgesic overuse: epidemiology and impact on
quality of life. Neurology 2004; 62: 1338–42.
withdrawal therapy. Despite the availability of several 10 Wiendels NJ, Knuistingh Neven A, Rosendaal FR, et al. Chronic treatment procedures, the relapse rate after successful frequent headache in the general population: prevalence and withdrawal therapy is still consistently about 25–30%. associated factors. Cephalalgia 2006; 26: 1434–42.
11 Aaseth K, Grande RB, Kvaerner KJ, Gulbrandsen P, Lundqvist C, Therefore, more research on the pathophysiology is Russell MB. Prevalence of secondary chronic headaches in a needed to identify diﬀ erent groups of patients and population-based sample of 30–44-year-old persons. The Akershus to individualise withdrawal therapy. It would be study of chronic headache. Cephalalgia 2008; 28: 705–13.
particularly helpful to identify the underlying genetic or 12 Wang SJ, Fuh JL, Lu SR, et al. Chronic daily headache in Chinese elderly: prevalence, risk factors, and biannual follow-up. Neurology psychological susceptibilities for MOH and to test these 2000; 54: 314–19.
www.thelancet.com/neurology Vol 9 April 2010
13 Prencipe M, Casini AR, Ferretti C, et al. Prevalence of headache in 38 Bahra A, Walsh M, Menon S, Goadsby PJ. Does chronic daily an elderly population: attack frequency, disability, and use of headache arise de novo in association with regular use of medication. J Neurol Neurosurg Psychiatry 2001; 70: 377–81.
analgesics? Headache 2003; 43: 179–90.
14 Katsarava Z, Schneeweiss S, Kurth T, et al. Incidence and predictors 39 Newman LC, Newman EB. Rebound abdominal pain: noncephalic for chronicity of headache in patients with episodic migraine. pain in abdominal migraine is exacerbated by medication overuse. Neurology 2004; 62: 788–90.
Headache 2008; 48: 959–61.
15 Bigal ME, Lipton RB. Excessive acute migraine medication use and 40 Ferrari A, Leone S, Tacchi R, et al. The link between pain patient migraine progression. Neurology 2008; 71: 1821–28.
and analgesic medication is greater in migraine than in rheumatic 16 Jensen R, Bendtsen L. Medication overuse headache in Scandinavia. disease patients. Cephalalgia 2009; 29: 31–37.
Cephalalgia 2008; 28: 1237–39.
41 Cupini LM, De Murtas M, Costa C, et al. Obsessive-compulsive 17 Bigal ME, Rapoport AM, Sheftell FD, Tepper SJ, Lipton RB. disorder and migraine with medication-overuse headache. Transformed migraine and medication overuse in a tertiary Headache 2009; 49: 1005–13.
headache centre—clinical characteristics and treatment outcomes. 42 Radat F, Creac‘h C, Swendsen JD, et al. Psychiatric comorbidity in Cephalalgia 2004; 24: 483–90.
the evolution from migraine to medication overuse headache. 18 Ravishankar K. Medication overuse headache in India. Cephalalgia Cephalalgia 2005; 25: 519–22.
2008; 28: 1223–26.
43 Atasoy HT, Atasoy N, Unal AE, Emre U, Sumer M. Psychiatric 19 Atasoy HT, Unal AE, Atasoy N, Emre U, Sumer M. Low income and comorbidity in medication overuse headache patients with education levels may cause medication overuse and chronicity in pre-existing headache type of episodic tension-type headache. migraine patients. Headache 2005; 45: 25–31.
Eur J Pain 2005; 9: 285–91.
20 Wiendels NJ, van Haestregt A, Knuistingh Neven A, et al. Chronic 44 Radat F, Creac’h C, Guegan-Massardier E, et al. Behavioral frequent headache in the general population: comorbidity and dependence in patients with medication overuse headache: quality of life. Cephalalgia 2006; 26: 1443–50.
a cross-sectional study in consulting patients using the DSM-IV 21 Kavuk I, Weimar C, Kim BT, et al. One-year prevalence and criteria. Headache 2008; 48: 1026–36.
socio-cultural aspects of chronic headache in Turkish immigrants 45 Grande RB, Aaseth K, Saltyte Benth J, Gulbrandsen P, Russell MB, and German natives. Cephalalgia 2006; 26: 1177–81.
Lundqvist C. The severity of dependence scale detects people with 22 Hagen K, Vatten L, Stovner LJ, Zwart JA, Krokstad S, Bovim G. medication overuse: the Akershus study of chronic headache. Low socio-economic status is associated with increased risk of J Neurol Neurosurg Psychiatry 2009; 80: 784–89.
frequent headache: a prospective study of 22718 adults in Norway. 46 Kaube H, May A, Pfaﬀ enrath V. Sumatriptan. BMJ 1994; 308: 1573–74.
Cephalalgia 2002; 22: 672–79.
47 Pini LA, Trenti T. Does chronic use of sumatriptan induce Classiﬁ cation Committee of the International Headache dependence? Headache 1994; 34: 600.
Society. Classiﬁ cation and diagnostic criteria for headache 48 Catarci T, Fiacco F, Argentino C, Sette G, Cerbo R. Ergotamine- disorders, cranial neuralgias and facial pain. Cephalagia 1988; induced headache can be sustained by sumatriptan daily intake. 8 (suppl 7): 1–96.
Cephalalgia 1994; 14: 374–75.
Classiﬁ cation Subcommittee of the International 49 Gaist D, Hallas J, Sindrup SH, Gram LF. Is overuse of sumatriptan Headache Society. The international classiﬁ cation of headache a problem? A population-based study. Eur J Clin Pharmacol 1996; disorders: 2nd edition. Cephalalgia 2004; 24 (suppl 1): 1–160.
25 Silberstein SD, Olesen J, Bousser MG, et al; International 50 Limmroth V, Kazarawa Z, Fritsche G, Diener HC. Headache after Headache Society. The International Classiﬁ cation of Headache frequent use of serotonin agonists zolmitriptan and naratriptan. Disorders, 2nd edition (ICHD-II)—revision of criteria for 8.2 Lancet 1999; 353: 378.
Medication-overuse headache. Cephalalgia 2005; 25: 460–65.
51 Evers S, Gralow I, Bauer B, et al. Sumatriptan and ergotamine Classiﬁ cation Committee. New appendix criteria open overuse and drug-induced headache: a clinicoepidemiologic study. for a broader concept of chronic migraine. Cephalalgia 2006; Clin Neuropharmacol 1999; 22: 201–06.
52 Bigal ME, Serrano D, Buse D, Scher A, Stewart WF, Lipton RB. 27 Zeeberg P, Olesen J, Jensen R. Medication overuse headache and Acute migraine medications and evolution from episodic to chronic chronic migraine in a specialized headache centre: ﬁ eld-testing migraine: a longitudinal population-based study. Headache 2008; proposed new appendix criteria. Cephalalgia 2009; 29: 214–220
28 Dodick DW, Silberstein SD. How clinicians can detect, prevent and 53 Feinstein AR, Heinemann LA, Dalessio D, et al. Do treat medication overuse headache. Cephalalgia 2008; 28: 1209–17.
caﬀ eine-containing analgesics promote dependence? A review 29 Ferrari A, Leone S, Vergoni AV, et al. Similarities and diﬀ erences and evaluation. Clin Pharmacol Ther 2000; 68: 457–67.
between chronic migraine and episodic migraine. Headache 2007; 54 Limmroth V, Katsarava Z, Fritsche G, Przywara S, Diener HC. 47: 65–72.
Features of medication overuse headache following overuse of 30 Evers S, Bauer B, Suhr S. Ergotamine-induced headache associated diﬀ erent acute headache drugs. Neurology 2002; 59: 1011–14.
with cluster headache. Neurology 1996; 46: 291.
55 Créac‘h C, Radat F, Mick G, et al. One or several types of triptan 31 Paemeleire K, Bahra A, Evers S, Matharu M, Goadsby PJ. overuse headaches? Headache 2009; 49: 519–28.
Medication-overuse headache in patients with cluster headache. 56 Ludolph AC, Husstedt IW, Schlake HP, Grotemeyer KH, Brune GG. Neurology 2006; 67: 109–13.
Chronic ergotamine abuse: evidence of functional impairment of 32 Evers S, Suhr B, Bauer B, Grotemeyer, Husstedt IW. A retrospective long ascending spinal tracts. Eur Neurol 1988; 28: 311–16.
long-term analysis of the epidemiology and features of drug- 57 Evers S, Bauer B, Grotemeyer KH, Kurlemann G, Husstedt IW. induced headache. J Neurol 1999; 246: 802–09.
Event-related potentials (P300) in childhood and adolescence primary 33 Bauer B, Evers S, Lindörfer HW, Schuierer G, Henningsen H, headache. J Child Neurol 1998; 13: 322–26.
Husstedt IW. Headache caused by a sphenoid mucocele but 58 Evers S, Schmidt F, Bauer B, Voss H, Grotemeyer KH, Husstedt IW. presenting as an ergotamine-induced headache. Headache 1997; The impact of ergotamine-induced headache and ergotamine 376: 460–62.
withdrawal on information processing. Psychopharmacology 1999; 34 Wolfe S, Van Stavern G. Characteristics of patients presenting with 142: 61–67.
ocular pain. Can J Ophthalmol 2008; 43: 432–34.
59 Barenbrock M, Spieker C, Witta J, et al. Reduced distensibility of the 35 Cady RK, Schreiber CP. Sinus problems as a cause of headache common carotid artery in patients treated with ergotamine. refractoriness and migraine chroniﬁ cation. Curr Pain Headache Rep Hypertension 1996; 28: 115–19.
2009; 13: 319–25.
60 Akova-Öztürk E, Husstedt IW, Ringelstein EB, Evers S. Carotid artery 36 Lance F, Parkes C, Wilkinson M. Does analgesic abuse cause dissection in ergotamine abuse. Headache 2004; 44: 930–32.
headaches de novo? Headache 1988; 28: 61–62.
61 Roon KI, Bakker D, van Poelgeest MI, van Buchem MA, Ferrari MD, 37 Wilkinson SM, Becker WJ, Heine JA. Opiate use to control bowel Middelkoop HA. The inﬂ uence of ergotamine abuse on motility may induce chronic daily headache in patients with psychological and cognitive functioning. Cephalalgia 2000; migraine. Headache 2001; 41: 303–09.
www.thelancet.com/neurology Vol 9 April 2010
62 Evers S, Voss H, Bauer B, Sörös P, Husstedt IW. Peripheral 85 Fumal A, Laureys S, Di Clemente L, et al. Orbitofrontal cortex autonomic potentials in primary headache and drug-induced involvement in chronic analgesic-overuse headache evolving from headache. Cephalalgia 1998; 18: 216–21.
episodic migraine. Brain 2006; 129: 543–50.
63 Feinstein AR, Heinemann LA, Curhan GC, et al. Relationship 86 Schmidt-Wilcke T, Leinisch E, Straube A, et al. Gray matter decrease between nonphenacetin combined analgesics and nephropathy: in patients with chronic tension type headache. Neurology 2005; a review. Ad Hoc Committee of the International Study Group on 65: 1483–86.
Analgesics and Nephropathy. Kidney Int 2000; 58: 2259–64.
87 Gerber WD, Miltner W, Niederberger U. The role of behavioral and 64 Mihatsch MJ, Khanlari B, Brunner FP. Obituary to analgesic social factors in the development of drug-induced headache. In: nephropathy—an autopsy study. Nephrol Dial Transplant 2006; Diener HC, Wilkinson M, eds. Drug-induced headache. Berlin: 21: 3139–45.
65 van der Woude FJ, Heinemann LA, Graf H, et al. Analgesics use and 88 Sances G, Galli F, Anastasi S, et al. Medication-overuse headache ESRD in younger age: a case-control study. BMC Nephrol 2007; 8: 15.
and personality: a controlled study by means of the MMPI-2. 66 Savrun F, Goksan B, Savrun M, Sahin R, Sahin S. Cerebral blood Headache 2010; 50: 198–209.
ﬂ ow changes in patients with probable medication-overuse 89 Zeeberg P, Olesen J, Jensen R. Discontinuation of medication headache. Funct Neurol 2008; 23: 83–86.
overuse in headache patients: recovery of therapeutic 67 Atasoy HT, Atasoy N, Unal AE, Sumer M. Sympathetic skin responsiveness. Cephalalgia 2006; 26: 1192–98.
response in migraineurs and patients with medication overuse 90 Rossi P, Jensen R, Nappi G, Allena M, the COMOESTAS headache. Headache 2004; 44: 305–10.
Consortium. A narrative review on the management of medication 68 Fusco BM, Colantoni O, Giacovazzo M. Alteration of central overuse headache: the steep road from experience to evidence. excitation circuits in chronic headache and analgesic misuse. J Headache Pain 2009; 10: 407–17.
Headache 1997; 37: 486–91.
91 Katsarava Z, Fritsche G, Muessig M, Diener HC, Limmroth V. 69 Ayzenberg I, Obermann M, Nyhuis P, et al. Central sensitization of Clinical features of withdrawal headache following overuse of the trigeminal and somatic nociceptive systems in medication triptans and other headache drugs. Neurology 2001; 57: 1694–98.
overuse headache mainly involves cerebral supraspinal structures. 92 Bøe MG, Salvesen R, Mygland A. Chronic daily headache with Cephalalgia 2006; 26: 1106–14.
medication overuse: a randomized follow-up by neurologist or PCP. 70 Cevoli S, Sancisi E, Grimaldi D, et al. Family history for chronic Cephalalgia 2009; 29: 855–63.
headache and drug overuse as a risk factor for headache 93 Andrasik F, Grazzi L, Usai S, Buse DC, Bussone G. chroniﬁ cation. Headache 2008; 48: 412–18.
Non-pharmacological approaches to treating chronic migraine with 71 Di Lorenzo C, Di Lorenzo G, Sances G, et al. Drug consumption in medication overuse. Neurol Sci 2009; 30 (suppl 1): S89–93.
medication overuse headache is inﬂ uenced by brain-derived 94 Altieri M, Di Giambattista R, Di Clemente L, et al. Combined neurotrophic factor Val66Met polymorphism. J Headache Pain 2009; pharmacological and short-term psychodynamic psychotherapy for 10: 349–55.
probable medication overuse headache: a pilot study. Cephalalgia 72 Cevoli S, Mochi M, Scapoli C, et al. A genetic association study of 2009; 29: 293–99.
dopamine metabolism-related genes and chronic headache with 95 Grazzi L, Andrasik F, D’Amico D, et al. Behavioral and drug abuse. Eur J Neurol 2006; 13: 1009–13.
pharmacologic treatment of transformed migraine with analgesic 73 Cevoli S, Marzocchi N, Capellari S, et al. Lack of association overuse: outcome at 3 years. Headache 2002; 42: 483–90.
between ﬁ ve serotonin metabolism-related genes and medication 96 Rossi P, Di Lorenzo C, Faroni J, Cesarino F, Nappi G. Advice alone overuse headache. J Headache Pain 2010; 11: 53–58.
vs. structured detoxiﬁ cation programmes for medication overuse 74 Sarchielli P, Rainero I, Coppola F, et al. Involvement of headache: a prospective, randomized, open-label trial in corticotrophin-releasing factor and orexin-A in chronic migraine transformed migraine patients with low medical needs. and medication-overuse headache: ﬁ ndings from cerebrospinal Cephalalgia 2006; 26: 1097–105.
ﬂ uid. Cephalalgia 2008; 28: 714–22.
97 Grazzi L, Andrasik F, Usai S, Bussone G. In-patient vs. day-hospital 75 Vieira DS, Naﬀ ah-Mazzacoratti Mda G, Zukerman E, withdrawal treatment for chronic migraine with medication overuse Senne Soares CA, Cavalheiro EA, Peres MF. Glutamate levels in and disability assessment: results at one-year follow-up. Neurol Sci cerebrospinal ﬂ uid and triptans overuse in chronic migraine. 2008; 29 (suppl 1): 161–63.
Headache 2007; 47: 842–47.
98 Paemelaire K, Crevitis L, Goadsby PH, Kaube H. Practical 76 Rainero I, Ferrero M, Rubino E, et al. Endocrine function is altered management of medication overuse headache. Acta Neurol Belg in chronic migraine patients with medication-overuse. Headache 2006; 106: 43–51.
2006; 46: 597–603.
99 Obermann M, Katsarava Z. Management of medication overuse 77 Srikiatkhachorn A, Govitrapong P, Limthavon C. Up-regulation of headache. Expert Rev Neurother 2007; 7: 1145–55.
5-HT2 serotonin receptor: a possible mechanism of transformed 100 Straube A, May A, Kropp P, et al. Therapie primärer chronischer migraine. Headache 1994; 34: 8–11.
Kopfschmerzen. Schmerz 2008; 22: 531–43.
78 Srikiatkhachorn A, Anthony M. Serotonin receptor adaptation in 101 Hagen K, Albretsen C, Vilming ST, et al. Management of patients with analgesic-induced headache. Cephalalgia 1996; medication overuse headache: 1-year randomized multicentre 16: 419–22.
open-label trial. Cephalalgia 2009; 29: 221–32.
79 Srikiatkhachorn A, Anthony M. Platelet serotonin in patients with 102 Diener HC, Bussone G, Van Oene JC, Lahaye M, Schwalen S, analgesic-induced headache. Cephalalgia 1996; 16: 423–26.
Goadsby PJ, TOPMAT-MIG-201(TOP-CHROME) Study Group. 80 Rossi C, Pini LA, Cupini ML, Calabresi P, Sarchielli P. Topiramate reduces headache days in chronic migraine: a Endocannabinoids in platelets of chronic migraine patients and randomized, double-blind, placebo-controlled study. Cephalalgia medication-overuse headache patients: relation with serotonin 2007; 27: 814–23.
levels. Eur J Clin Pharmacol 2008; 64: 1–8.
103 Bøe MG, Mygland A, Salvesen R. Prednisolone does not reduce 81 Ayzenberg I, Obermann M, Leineweber K, et al. Increased activity withdrawal headache: a randomized, double-blind study. Neurology of serotonin uptake in platelets in medication overuse headache 2007; 69: 26–31.
following regular intake of analgesics and triptans. J Headache Pain 104 Krymchantowski AV, Barbosa JS. Prednisone as initial treatment of 2008; 9: 109–12.
analgesic-induced daily headache. Cephalalgia 2000; 20: 107–13.
82 Anselmi B, Tarquini R, Panconesi A, et al. Serum beta-endorphin 105 Pageler L, Katsarava Z, Diener HC, Limmroth V. Prednisone vs. increase after intravenous histamine treatment of chronic daily placebo in withdrawal therapy following medication overuse headache. Recenti Prog Med 1997; 88: 321–24.
headache. Cephalalgia 2008; 28: 152–56.
83 Schoenen J, Malais P, Dresse A. Urinary excretion of 106 Andersson PG. Ergotamine headache. Headache 1975; 15: 118–21.
3 methoxy-4-hydroxyphenylglycol (MHPG) in headache patients: 107 Tfelt-Hansen P, Krabbe AA. Ergotamine. Do patients beneﬁ t from clinical correlations. Cephalalgia 1987; 7 (suppl) 6: 29–31.
withdrawal? Cephalalgia 1981; 1: 29–32.
84 Hering R, Gardiner I, Catarci T, Whitmarsh T, Steiner T, 108 Ala-Hurula V, Myllylä V, Hokkanen E. Ergotamine abuse: results of de Belleroche J. Cellular adaptation in migraineurs with chronic ergotamine discontinuation, with special reference to the plasma daily headache. Cephalalgia 1993; 13: 261–66.
concentrations. Cephalalgia 1982; 2: 189–95.
www.thelancet.com/neurology Vol 9 April 2010
109 Henry P, Dartigues JF, Benetier MP, Lucas J, Duplan B, Jogeix M. 121 Bøe MG, Salvesen R, Mygland A. Chronic daily headache with Ergotamine- and analgesic-induced headaches. In: Cliﬀ ord RF, ed. medication overuse: predictors of outcome 1 year after withdrawal Migraine. London: Karger, 1985: 197–205.
therapy. Eur J Neurol 2009; 16: 705–12.
110 Granella F, Farina S, Malferrari G, Manzoni GC. Drug abuse in 122 Ghiotto N, Sances G, Galli F, et al. Medication overuse headache chronic headache: a clinico-epidemiologic study. Cephalalgia 1987; and applicability of the ICHD-II diagnostic criteria: 1-year follow-up 7: 15–19.
study (CARE I protocol). Cephalalgia 2009; 29: 233–43.
111 Baumgartner C, Wessely P, Bingol C, Maly J, Holzner F. Long-term 123 Zidverc-Trajkovic J, Pekmezovic T, Jovanovic Z, et al. Medication prognosis of analgesic withdrawal in patients with drug-induced overuse headache: clinical features predicting treatment outcome headaches. Headache 1989; 19: 510–14.
at 1-year follow-up. Cephalalgia 2007; 27: 1219–25.
112 Hering R, Steiner TJ. Abrupt outpatient withdrawal of medication 124 Zeeberg P, Olesen J, Jensen R. Probable medication-overuse in analgesic abusing migraineurs. Lancet 1991; 337: 1442–43.
headache: the eﬀ ect of a 2-month drug-free period. Neurology 2006; 113 Silberstein SD, Silberstein JR. Chronic daily headache: longterm 66: 1894–98.
prognosis following inpatient treatment with repetitive iv DHE. 125 Wang SJ, Fuh JL, Lu SR, Juang KD. Chronic daily headache in Headache 1992; 32: 439–45.
adolescents: prevalence, impact, and medication overuse. 114 Pini LA, Bigarelli M, Vitale G, Stemieri E. Headache associated with Neurology 2006; 66: 193–97.
chronic use of analgesics: a therapeutic approach. Headache 1996; 126 Pakalnis A, Butz C, Splaingard D, Kring D, Fong J. Emotional 36: 433–39.
problems and prevalence of medication overuse in pediatric chronic 115 Schnider P, Aull S, Baumgartner C, et al. Long-term outcome of daily headache. J Child Neurol 2007; 22: 1356–59.
patients with headache and drug abuse after inpatient withdrawal: 127 Kossoﬀ EH, Mankad DN. Medication-overuse headache in children: ﬁ ve-year follow up. Cephalalgia 1996; 16: 481–85.
is initial preventive therapy necessary? J Child Neurol 2006; 116 Suhr B, Evers S, Bauer B, Gralow I, Grotemeyer KH, Husstedt IW. 21: 45–48.
Drug-induced headache: long-term results of stationary versus 128 Hershey AD. Chronic daily headache in children. ambulatory withdrawal therapy. Cephalalgia 1999; 19: 44–49.
Expert Opin Pharmacother 2003; 4: 485–91.
117 Fritsche G, Eberl A, Katsarava Z, Limmroth V, Diener HC. 129 Hering-Hanit R, Gadoth N. Caﬀ eine-induced headache in children Drug-induced headache: long-term follow-up of withdrawal therapy and adolescents. Cephalalgia 2003; 23: 332–35.
and persistence of drug misuse. Eur Neurol 2001; 45: 229–35.
130 Dyb G, Holmen TL, Zwart JA. Analgesic overuse among 118 Katsarava Z, Muessig M, Dzagnidze A, Fritsche G, Diener HC, adolescents with headache: the Head-HUNT-Youth Study. Limmroth V. Medication overuse headache: rates and predictors for Neurology 2006; 66: 198–201.
relapse in a 4-year prospective study. Cephalalgia 2005; 25: 12–15.
131 Wang SJ, Juang KD, Fuh JL, Lu SR. Psychiatric comorbidity and 119 Relja G, Granato A, Bratina A, Antonello RM, Zorzon M. Outcome suicide risk in adolescents with chronic daily headache. Neurology of medication overuse headache after abrupt in-patient withdrawal. 2007; 68: 1468–73.
Cephalalgia 2006; 26: 589–95.
120 Rossi P, Faroni JV, Nappi G. Medication overuse headache: predictors and rates of relapse in migraine patients with low
medical needs. A 1-year prospective study. Cephalalgia 2008;
www.thelancet.com/neurology Vol 9 April 2010
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,