Name der Studie Titel der abgelaufenden klinischen Studien Stand der Studie A Phase 3 Randomized, Double-blind, Parallel-group, Multi-center Study of the Safety and Efficacy of Apixaban for Prophylaxis of Venous Thromboembolism in Acutely III Medical Subjects During and Following HospitalizationA Safety and Efficacy Trial Evaluating the Use of Apixaban for the extended Treatment of Deep
Treatment of medication overuse headache guideline of the efns headache panelEuropean Journal of Neurology 2011, 18: 1115–1121 E F N S G U I D E L I N E S / C M E A R T I C L E Treatment of medication overuse headache – guideline of theEFNS headache panel S. Eversa and R. JensenbaDepartment of Neurology, University of Mu¨nster, Mu¨nster, Germany; and bDanish Headache Center, Department of Neurology, GlostrupHospital, University of Copenhagen, Copenhagen, Denmark Background: Medication overuse headache is a common condition with a population- based prevalence of more than 1–2%. Treatment is based on education, withdrawal treatment (detoxiﬁcation), and prophylactic treatment. It also includes management of withdrawal headache.
Aims: This guideline aims to give treatment recommendations for this headache.
Materials and methods: Evaluation of the scientiﬁc literature.
Results: Abrupt withdrawal or tapering down of overused medication is recommended,the type of withdrawal therapy is probably not relevant for the outcome of the patient.
However, inpatient withdrawal therapy is recommended for patients overusing opioids,benzodiazepine, or barbiturates. It is further recommended to start individualizedprophylactic drug treatment at the ﬁrst day of withdrawal therapy or even before. Theonly drug with moderate evidence for the prophylactic treatment in patients withchronic migraine and medication overuse is topiramate up to 200 mg. Corticosteroids(at least 60 mg prednisone or prednisolone) and amitriptyline (up to 50 mg) are pos-sibly eﬀective in the treatment of withdrawal symptoms. Patients after withdrawaltherapy should be followed up regularly to prevent relapse of medication overuse.
Discussion and conclusion: Medication overuse headache can be treated according toevidence-based recommendations.
This guideline aims to give recommendations for the The classiﬁcation of the IHS provides diagnostic crite- treatment of medication overuse headache (MOH) as ria for chronic headache which is accompanied by the classiﬁed by the International Headache Society (IHS) overuse of acute headache drugs such as analgesics, . Although this headache disorder is frequent and a triptans, and opioids (Table 1). In the ﬁrst edition of major problem in the treatment of patients with chronic the IHS classiﬁcation, this headache disorder was headache, placebo- or sham-controlled double-blind deﬁned as drug-induced headache implicating that the trials for a speciﬁc treatment of this condition are frequent drug intake itself is the cause of the headache almost completely missing. Nearly, all published trials . In the present classiﬁcation, medication overuse are underpowered or have a high number of dropouts.
with all its somatic and psychological implications is Therefore, these guidelines are based on publications regarded as an association and possibly not the only with a low level of evidence and on expert consensus. A cause of chronic headache . However, it has soon brief clinical description of this potentially preventable become obvious that some subtypes were missing and and treatable type of headache disorder is included.
that headache features of MOH cannot be deﬁned ingeneral. Therefore, a revision of these diagnostic crite-ria was published in 2005 . These criteria are validuntil today although a further revision developed for Correspondence: Prof. S. Evers, MD PhD, Department of Neurology,University of Mu¨nster, Albert-Schweitzer-Str. 33, 48129 Mu¨nster, research purposes has been published in 2006 .
Germany (tel.: +49 251 8348196; fax: +49 251 8348181; e-mail The purpose of this article is to give recommenda- tions for the speciﬁc management of MOH including This is a Continuing Medical Education article, and can be found with the treatment of withdrawal headache. The recom- corresponding questions on the Internet at http://www.efns.org/EFNS mendations are based on the scientiﬁc evidence from Continuing-Medical-Education-online.301.0.html. Certiﬁcates forcorrectly answering the questions will be issued by the EFNS.
clinical trials and on the expert consensus by the Ó 2011 The Author(s)European Journal of Neurology Ó 2011 EFNS Table 1 Current diagnostic criteria of the International Headache Society for medication overuse headache (MOH) A. Headachea present on ‡15 days/month fulﬁlling criteria C and DB. Regular overuseb for ‡3 months of one or more drugs that can be taken for acute and/or symptomatic treatment of headachecC. Headache has developed or markedly worsened during medication overuseD. Headache resolves or reverts to its previous pattern within 2 months after discontinuation of overused medicationd aThe headache associated with medication overuse is variable and often has a peculiar pattern with characteristics shifting, even within the sameday, from migraine like to those of tension-type headache.
bOveruse is deﬁned in terms of duration and treatment days per week. What is crucial is that treatment occurs both frequently and regularly, i.e., on2 or more days each week. Bunching of treatment days with long periods without medication intake, practised by some patients, is much less likelyto cause MOH and does not fulﬁll criterion B.
cMOH can occur in headache-prone patients when acute headache medications are taken for other indications.
dA period of 2 months after cessation of overuse is stipulated in which improvement (resolution of headache, or reversion to its previous pattern)must occur if the diagnosis is to be deﬁnite. Prior to cessation, or pending improvement within 2 months after cessation, the diagnosis 8.2.8Probable MOH should be applied. If such improvement does not then occur within 2 months, this diagnosis must be discarded.
Ergotamine intake on ‡10 days/month on a regular basis for >3 months Triptan intake (any formulation) on ‡10 days/month on a regular basis for >3 months Intake of simple analgesics on ‡15 days/month on a regular basis for >3 months Opioid intake on ‡10 days/month on a regular basis for >3 months 8.2.5 Combination analgesic-overuse headache Intake of combination analgesic medicationsa on ‡10 days/month on a regular basis for >3 months 8.2.6 MOH attributed to the combination of acute medications Intake of any combination of ergotamine, triptans, analgesics, and/or opioids on ‡10 days/month on a regular basis for >3 months withoutoveruse of any single class aloneb 8.2.7 Headache attributed to other medication overuse Regular overusec for >3 months of a medication other than those described earlier A. Headache fulﬁlling criteria A, C, and D for 8.2 MOH B. Medication overuse fulﬁlling criterion B for any one of the subforms 8.2.1–82.7 1. Overused medication has not yet been withdrawn 2. Medication overuse has ceased within the last 2 months, but headache has not so far resolved or reverted to its previous pattern aCombination typically implicated are those containing simple analgesics combined with opioids, butalbital, and/or caffeine.
bThe speciﬁc subform(s) 8.2.1–8.2.5 should be diagnosed if criterion B is fulﬁlled in respect of any one or more single class(es) of these medications.
cThe deﬁnition of overuse in terms of treatment days per week is probably to vary with the nature of the medication.
respective task force of the EFNS. The deﬁnitions of headache disorders. In addition, a review book was the recommendation levels follow the EFNS criteria .
A literature search was performed using the reference The development of MOH is mainly reported in databases MedLine, Science Citation Index, and the patients with a primary headache disorder such as Cochrane Library; the key words used were ÔheadacheÕ migraine and tension-type headache but has also been together with the term Ômedication overuseÕ or Ôdrug- reported in smaller series of secondary headaches inducedÕ (last search in January 2011). All articles [7–11]. For cluster headache, studies have been pub- lished showing that these patients can also fulﬁll the considered when they described a controlled trial or a criteria for MOH [12,13]. However, most of these case report or series on the treatment of one of these patients had migraine as a comorbid headache or mi- European Journal of Neurology Ó 2011 EFNS European Journal of Neurology 18, 1115–1121 graine in their family history, and many cluster patients nausea, vomiting, arterial hypotension, tachycardia, with headache take analgesics, ergotamine derivatives, sleep disturbances, restlessness, anxiety, and nervous- or triptans on a daily basis without MOH. Patients with ness. These symptoms normally last between 2 and other pain conditions such as rheumatic diseases and no 10 days but can persist for up to 4 weeks. The with- headache disorder do not develop chronic headache de drawal headache was shorter in patients having taken novo when taking analgesics because of their pain triptans (mean 4.1 days) than ergotamine derivatives (mean 6.7 days) or NSAIDs (mean 9.5 days) .
The population-based 1-year prevalence of MOH in The outcome of withdrawal therapy in patients with diﬀerent countries ranges from 0.7% to 1.7% with a MOH followed up by a neurologist as compared to a female preponderance between 62% and 92% .
primary care physician did not diﬀer signiﬁcantly for The incidence of MOH has not been studied in speciﬁc population-based studies. In a study on episodic headache days . Therefore, it is suggested that a migraineurs, the 1-year incidence of chronic headache primary care physician can follow these patients after including MOH was 14% . Amongst all patients in detoxiﬁcation, which was made in this study in hospital, headache clinics or centers of tertiary care, patients as well as a neurologist or a pain specialist.
with MOH are one of the largest patient group. In With regard to non-pharmacological approaches of Europe up to 30% and in the USA even more than treating MOH, combined short-term psychodynamic 50% of the patients in such centers present with MOH psychotherapy and pharmacological therapy improved [18,20]. In India, for example, only 3.1% of the headache in MOH, and the combination of both had patients in a headache clinic fulﬁll the criteria for been superior to pharmacological therapy alone for reducing long-term relapses and reduction in quality of In principle, all acute drugs for the treatment of life in a non-randomized study . In another study, headache have been described to cause MOH (i.e., 120 uncomplicated patients with MOH were treated with ergotamine derivatives, barbiturates, triptans, analge- three diﬀerent modalities: (i) only strong advice to sics both simple and combined, opioids, benzodiaze- withdraw overused medication; (ii) standard outpatient pines; possibly also caﬀeine). Today, simple analgesics detoxiﬁcation programme (rapid withdrawal of over- and triptans are the most frequent drugs taken by used medication plus oral prednisolone for 8 days plus personalized prophylactive drugs); (iii) inpatient pro-gramme (rapid withdrawal of overused medication plusoral prednisolone for 8 days plus personalized prophyl- active drugs plus parenteral ﬂuid and antiemetics plus There is evidence, although not overwhelming and close observation for 8 days). The percentages of unanimously shown in prospective trials, that with- patients achieving successful withdrawal and the head- drawal therapy is the best treatment for MOH.
ache frequency were not diﬀerent between the groups However, all experts and headache centers agree that during the follow-up period of 60 days after withdrawal withdrawal therapy should be oﬀered to patients with MOH. The goal of this treatment is not only to detoxify A direct comparison between inpatient withdrawal the patients and to stop the chronic headache but also, and outpatient withdrawal treatment showed that both probably, to improve responsiveness to acute or pro- methods revealed a signiﬁcant decrease in headache days per month after 12 months and a reduction in thescores of migraine disability without superiority of onemethod . Following this study, the outpatient with- drawal is less expensive and as successful in a motivated The recommended procedures for withdrawal of patient group than inpatient withdrawal. Advantages of patients with MOH vary, and no study has compared the inpatient withdrawal are the close monitoring of abrupt withdrawal treatment with tapered withdrawal medication intake and the clinical state, professional in prospective randomized trials. Most headache spe- psychological support, an immediate treatment of cialists favor the abrupt discontinuation of pain withdrawal symptoms, and eventually the administra- medication under the impression that abrupt with- tion of intravenous drugs. Overusing opioids, barbitu- drawal is associated with faster resolution of the drug- rates, or benzodiazepines, psychological problems, induced pain-coping behavior . However, tapered severe medical comorbidities, severe withdrawal symp- withdrawal seems to be recommendable for opioids, for toms (e.g., vomiting, status migrainosus), or previous barbiturates, and for benzodiazepines. Main with- medication withdrawal failure are reasons for inpatient drawal symptoms are worsening of the headache, treatment according to expert consensus or national Ó 2011 The Author(s)European Journal of Neurology Ó 2011 EFNS European Journal of Neurology 18, 1115–1121 guidelines [30–32]. However, this recommendation is patients (between 63% and 69% of all patients in the not supported by randomized prospective trials.
diﬀerent treatment arms) is given, the studies give evi- A recent prospective, multicenter study investigated dence that onabotulinum toxin A is eﬃcacious in the three relatively small groups: (i) only personalized pre- reduction of headache days in MOH. In summary, it is ventive medication from day 1 (n = 17); (ii) abrupt suggested that detoxiﬁcation prior to initiating pro- withdrawal plus rescue medication (n = 20); (iii) no phylactic therapy may not be required in all patients preventive medication plus no advice to stop overused with MOH , whereas other studies support the drugs (n = 19) . The primary end-point, change in importance of initial detoxiﬁcation [20,23,37].
headache days, did, however, not diﬀer signiﬁcantlybetween all three groups. Because of the more pro- nounced reduction in the headache index of the ﬁrstgroup in comparison with the second group, there Because most drugs helpful for the treatment of with- might be an advantage for a personalized preventive medication without abrupt withdrawal. In another corticosteroids were regarded as an option for the study, advice alone was successful as withdrawal ther- treatment of withdrawal headache [40,41]. The only apy in nearly all patients with simple MOH but sig- controlled, randomized, double-blind study that inves- niﬁcantly less successful in patients with complicated tigated oral prednisolone during the ﬁrst 6 days after MOH . Further larger, prospective trials are neces- medication withdrawal revealed no eﬀect on a com- bined primary end-point. Of total 97 patients, 49 Studies on a speciﬁc preventive therapy of MOH are received prednisolone (60 mg on days 1 and 2, 40 mg missing. Therefore, the choice of the preventive agent in on days 3 and 4, and 20 mg on days 5 and 6) and 48 MOH should be based on the primary headache (e.g., placebo . Conversely, a large open-label trial on migraine vs. tension-type headache), the possible side patients with chronic daily headache and medication eﬀects of the drugs, the comorbidities, and the patientÕs overuse showed that treatment with 60 mg prednisone preference and previous therapeutic experience. Several for 2 days and tapering down by 20 mg every other day open-label trials showed positive eﬀects of diﬀerent eﬀectively reduced rebound headache and withdrawal substances such as valproic acid and topiramate in the symptoms . Recently, in a small proof-of-concept prophylactic treatment of chronic daily headache with study, nine patients each with MOH received either excessive medication intake. A double-blind trial in placebo or 100 mg prednisone for 5 days . The patients with the speciﬁc diagnosis of chronic migraine duration of withdrawal headache was signiﬁcantly and medication overuse showed a signiﬁcant reduction lower in the prednisone group as compared to the in the mean number of migraine days per month by placebo group. Taken these results together, there topiramate (range 50–200 mg/day) in comparison with might be an eﬃcacy of corticosteroids on withdrawal placebo ()3.5 ± 6.3 vs. )0.2 ± 4.7; P < 0.05). How- symptoms in patients with MOH but high-quality ever, side eﬀects were reported by 75% of the patients placebo-controlled trials are needed.
in the topiramate group compared with 37% in the There are no other controlled trials on the speciﬁc placebo group . The headache reduction was nev- treatment of withdrawal headache or of other symp- ertheless not big enough to change the chronic head- toms during withdrawal therapy. One open study ache into an episodic form. In a similar study on suggested the combination of intravenous hydration, chronic migraine, topiramate achieved a signiﬁcant dexamethasone, metoclopramide, and benzodiazepines reduction in migrainous days per month by 6.4 as for 7–15 days . Very early studies suggested that compared to placebo which achieved a reduction by also (subcutaneous) sumatriptan, naproxen (500 mg), and amitriptyline (10–50 mg) were eﬀective in amelio- In a large-scale study of 335 patients with MOH from rating withdrawal headache [40,45,46]. However, all the Danish Headache centre, where abrupt detoxiﬁca- these studies were not placebo controlled. Therefore, by tion was initiated, the headache frequency was reduced expert consensus, headache drugs and analgesics are by 67% in migraine patients and by 37% in those with not recommended for the treatment of headache during combined migraine and tension-type headache after a 2- withdrawal therapy except single intravenous adminis- month observation period without prophylactic medi- cation . In a recent project with two large studies onthe eﬃcacy of onabotulinum toxin A in the treatment of chronic migraine, also patients with medication overusewere treated . Although no speciﬁc data on the The relapse rate of MOH is about 30% (range between eﬃcacy of onabotulinum toxin in this speciﬁc group of 14% and 41%) after 1 year regardless whether inpa- European Journal of Neurology Ó 2011 EFNS European Journal of Neurology 18, 1115–1121 Table 2 Recommendations for the treatment of medication overuse headache (MOH). The level of recommendation is classiﬁed as follows Level A: established as effective, ineffective, or harmful by at least one convincing class I study or at least two consistent, convincing class II studiesLevel B: probably effective, ineffective, or harmful by at least one convincing class II study or overwhelming class III evidenceLevel C: possibly effective, ineffective, or harmful by at least two convincing class III studiesGood practice point: lack of evidence but consensus within the task force 1) Patients with MOH should be offered advice and teaching to encourage withdrawal treatment. (B)2) There is no general evidence whether abrupt or tapering withdrawal treatment should be preferred. For the overuse of analgesics, ergotamine derivatives, or triptans, abrupt withdrawal is recommended. For the overuse of opioids, benzodiazepines, or barbiturates, tapering down of themedication should be offered. (good practice point) 3) The type of withdrawal treatment (inpatient, outpatient, advice alone) does not inﬂuence the success of the treatment and the relapse rate in 4) In patients with opioid, benzodiazepine, or barbiturate overuse, with severe psychiatric or medical comorbidity or with failure of a previous outpatient withdrawal treatment, inpatient withdrawal treatment should be offered. (good practice point) 5) Individualized preventive medication should be started at the ﬁrst day of withdrawal treatment or even before if applicable. (C)6) Topiramate 100 mg (up to 200 mg maximum) per day is probably effective in the treatment of MOH. (B)7) Corticosteroids (at least 60 mg prednisone or prednisolone) and amitriptyline (up to 50 mg) are possibly effective in the treatment of withdrawal 8) Patients after withdrawal therapy should be followed up regularly to prevent relapse of medication overuse. (good practice point) tient, outpatient, or advice alone treatment were Specific pattern in children and adolescents applied . Further, the relapse rates do not diﬀersigniﬁcantly when a short or a long observation period Several studies showed that MOH also exists in children is used, and most studies indicate that the eventual and adolescents . Population-based epidemiological relapse occurs at an early stage (i.e., within few months) studies detected a 1-year prevalence of 0.3–0.5% in after detoxiﬁcation. In one study, for example, the adolescents all of them overusing over the counter relapse rate was 23% both after 2 months and after (OTC) analgesics (mainly combined analgesics) [54,55].
1 year in the same sample;  in another example, the Children also beneﬁt from withdrawal therapy .
relapse rate was 41% after 1 year and 44% after 4 years However, only very few data are available on the best . Overall, the detoxiﬁcation is fairly successful in treatment in this age group. One month after with- most patients, and all patients with MOH should be drawal therapy, about 53% of all children had a informed and encouraged to discontinue their overuse.
reduction in headache frequency by more than 90% In the general population, simple advice regarding regardless whether they were on preventive medication MOH was suﬃcient to result in a successful treatment or not; the only predictor for a poor outcome after of MOH in 76% of all patients after 1.5 years .
withdrawal therapy was a duration of MOH longer In an Italian study on diﬀerent ways of withdrawal therapy, a long duration of migraine before medicationoveruse, a higher frequency of migraine after with- drawal therapy, and a greater number of previouspreventive treatments were associated with a higher risk As described earlier, only very few controlled and/or for relapse of MOH . In other studies, predictors of randomized trials are available to give evidence-based relapse were male sex, intake of combination analgesics recommendations for the treatment of MOH. There- after withdrawal therapy, nicotine and alcohol con- fore, the conclusions of this guideline are of low evi- sumption, and taking the former medication again after dence or are good practice points as agreed by expert withdrawal therapy [51,52]. Recently, use of codeine- consensus. A summary of our clinical recommendations containing drugs, low self-reported sleep quality, and high self-reported bodily pain as measured by thequality of life tool SF-36 were predictors for a poor outcome . In some studies, the prognosis was betterfor patients with migraine as the underlying primary 1. Headache Classiﬁcation Subcommittee. The international headache disorder than for patients with tension-type classiﬁcation of headache disorders. Cephalalgia 2004;24(Suppl. 1): 1–160.
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Louis Miller Wins Common Wealth Award Carver Mead Wins Prestigious Invention Prize the National Institute of Allergy andInfectious Diseases (NIAID), receivedthe 1999 Common Wealth Award forscience at the California Institute ofTechnology, was awarded the 1999 Louis Miller 1965 when he was assigned toBangkok, Thailand, with the U.S. S I G M A X I T O D A Y An Interview with