Medication Overuse Headache

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1 Curr Neurol Neurosci Rep (2015) 15:509 DOI /s x HEADACHE (R HALKER, SECTION EDITOR) Medication Overuse Headache Valerie Cheung & Farnaz Amoozegar & Esma Dilli Published online: 15 November 2014 # Springer Science+Business Media New York 2014 Abstract Medication overuse headache (MOH) is a common and disabling headache disorder. It has a prevalence of about 1 2 % in the general population. The International Classification of Headache Disorders 3rd edition (beta version) has defined MOH as a chronic headache disorder in which the headache occurs on 15 or more days per month due to regular overuse of medication. These headaches must have been present for more than 3 months. The pathophysiology is complex and not completely known. It involves genetic and behavioural factors. There is evidence that cortical spreading depression, trigeminovascular system and neurotransmitters contribute to the pain pathway of MOH. The treatment of MOH includes patient education, stopping the offending drug(s), rescue therapy for withdrawal symptoms and preventative therapy. Relapse rates for MOH are high at 41 %. MOH can severely impact quality of life, so it is important to identify patients who are at risk of analgesic overuse. Keywords Medication overuse headache. Rebound headache. Chronic daily headache. Opioids. Triptans. Combination analgesics. NSAIDS This article is part of the Topical Collection on Headache V. Cheung : E. Dilli (*) Gordon and Leslie Diamond Health Center-8219, University of British Columbia, 2775 Laurel Street, Vancouver, BC V5Z 1M9, Canada F. Amoozegar Clinical Neurosciences Headache Program, University of Calgary, South Health Campus Front Street S.E., Calgary, AB T3M 1M9, Canada Introduction Medication overuse headache (MOH) is a headache disorder in which the treatment for headaches has become its curse. It is a relatively new diagnosis and was first reported by Peters and Horton in 1951 [1]. They described a chronic headache in a subset of patients with migraine and tension headaches, in which the withdrawal of medication led to fewer headaches. These headaches were called ergotamine headaches because they were seen in patients who took ergots [2]. In the 1960s, it was discovered that patients on barbiturates and caffeine could also present with headaches related to medication use [3]. More studies in the 1980s showed that headaches could occur with simple and combined analgesics. Drug-induced headaches were re-defined to a broader concept that included many treatments and headache types [4]. In 1988, the first International Classification of Headache Disorders (ICHD) criteria called this disorder headache induced by chronic substance use or exposure. They stated that patients must have headaches on at least 15 days per month, use medications for at least 3 months at a certain minimum dose, and have their headaches subside after 1 month of withdrawal [5]. In the 1990s, triptans became popular and more patients developed chronic headaches secondary to medications [4]. However, it was not until 2004 that the term medication overuse headache was introduced in the ICHD-2 criteria [1]. Several revisions have been made based on our current understanding of MOH [6]. The most recent MOH criteria published is the ICHD-3 beta version. MOH is defined as a pre-existing primary headache that has become markedly worse, or has evolved into a new type of headache, in association with medication overuse [6]. More specifically, the headache should occur on at least 15 days per month, and the patient must have overused medication for at least 3 months. It usually but does not always resolve after the offending medication is stopped [6].

2 509, Page 2 of 8 Curr Neurol Neurosci Rep (2015) 15:509 MOH is sub-classified by drug type; these classes include ergotamine, triptan, simple analgesic, opioid, combination, MOH attributed to multiple drug classes not individually overused, MOH attributed to unverified overuse of multiple drug classes and MOH attributed to other medications [6]. Drug overuse is defined as use of a drug for at least 10 to 15 days per month, and the length of time varies by drug type [6]. MOH is an important disorder because it can severely impact a patient s quality of life [4]. In fact, patients suffering from MOH have a poorer quality of life than those with episodic headaches or even chronic daily headaches [7]. It is an expensive disease, with a high economic burden on society [4]. Some of the finances associated with MOH include missed work days, emergency room visits, hospital admissions and unnecessary tests [8 ]. MOH patients report greater disability, lower productivity and lower SF-36 scores [7]. The goal of our article is to review the pathophysiology, clinical presentation and treatment of MOH. Epidemiology The prevalence of MOH is about 1 2 % of the general population [9, 10 ]. This number varies amongst studies and is further confounded by the evolving definition of MOH over the past 20 years. The prevalence usually ranges from 0.5 to 2.5 % in adults, but outliers of 7.2 and 4.9 % have been reported from Russia and Iran, respectively [1, 11, 12]. The prevalence is much higher in tertiary care and headache referral centres, where up to 30 % of headache patients in Europe and 50 % in the USA have MOH [4]. Women are affected more often than men, and this has been consistent in all but one study [9, 12]. This phenomenon may be related to the higher prevalence of migraine in the female population. MOH is most commonly seen in those aged 40 to 45, but other age groups can be affected [10 ]. There are fewer adolescents with MOH compared to adults, possibly due to the prescribing practices for adolescents. In Norway and Taiwan, 0.2 and 0.3 % of teenagers had MOH, respectively, but the same studies showed that MOH occurred in 1.0 and 1.1 % of adults, respectively [1, 13 16]. The prevalence in the elderly in Taiwan was 1.0 % [1, 17]. MOH occurs in both developing and wealthy nations. However, drug profiles may differ as triptan use is higher in countries with more financial resources [10 ]. Drug use has also changed over time. From 1990 to 2005, an American study showed a decrease in ergot use and an increase in triptan use [18]. Pathophysiology The pathophysiology of MOH is not completely known, but genetic factors may play a role [4]. The risk of MOH is almost three times greater in those with a family history of MOH [19]. Patients with MOH are also more likely to have relatives who overuse drugs or have substance abuse problems [19]. MOH happens to those who have an underlying headache disorder, in particular migraine, suggesting a genetic predisposition [10 ]. One study revealed that patients with arthritis who consumed large amounts of analgesics did not develop more headaches unless they already had a history of migraines [20]. Another study in post-operative ulcerative colitis patients who had a colectomy similarly found that only patients with migraines in the past developed a chronic headache in response to medication overuse [21]. One possibility is that serotonin and dopamine transporter polymorphisms could lead to MOH, but the data is conflicting [22]. Medication overuse headache may also be a biobehavioural disorder [23]. Behaviours that can perpetuate medication overuse include fear of headaches, anticipatory anxiety, obsessional drug taking and psychological drug dependence [23]. A lack of awareness of MOH may contribute as most patients take the acute medications for pain to function without understanding the consequence of medication overuse. According to a functional magnetic resonance imaging (fmri) study, MOH patients have dysfunctions in the mesocorticolimbic dopamine circuit, specifically in the ventromedial prefrontal cortex and the substantia nigra/ventral tegmental area. The ventral tegmental area plays a role in the brain reward circuit and likely in drug dependence [24]. A separate FDG-PET study in MOH patients showed hypometabolism in structures that process pain, including the bilateral thalamus, anterior cingulate gyrus, insula/ventral striatum, right inferior parietal lobe and orbitofrontal cortex [25]. After withdrawal of the overused drug, all the changes reversed except for hypometabolism in the orbitofrontal cortex. Interestingly, substance abuse patients also have decreased activity in the orbitofrontal cortex [25]. The pathophysiology of migraine begins with cortical spreading depression, and this also appears to occur in MOH. Neurophysiology studies demonstrated that neurons are excitable in the somatosensory and visual cortices of MOH patients [26]. In rats, chronic acetaminophen or ergot use increased the frequency of cortical spreadingdepression(csd)[27, 28]. Cortical changes are also evident in MOH. Research using median nerve sensory evoked potentials has shown that the somatosensorycortexissensitizedinmohpatients.theeffect was greater when patients took non-steroidal anti-inflammatory drugs (NSAIDs) [29]. On fmri, there was decreased activity in the primary somatosensory cortex and other pain-processing structures of MOH patients [27 ]. After 6 months of drug withdrawal, the imaging changes reversed [30]. Thus, cortical spreading depression and altered activity of the somatosensory cortex mayresultinmoh.

3 Curr Neurol Neurosci Rep (2015) 15:509 Page 3 of 8, 509 Another mechanism by which MOH may act is through the trigeminovascular system, and we will review the basic anatomy here. The first-order neuron includes the trigeminal ganglion and innervates pain-sensitive structures like the cranial vessels, meninges and pericardial muscles. It releases calcitonin gene-related peptide (CGRP), resulting in the dilation of cranial vessels and increased sensitivity of perivascular nociceptors. It then travels to the somatosensory cortex by synapsing with the second- and third-order neurons at the trigeminocervical complex (TCC) and ventral posteromedial (VPM) nucleus of the thalamus, respectively. Chronic activation of the trigeminovascular system results in the transcription of proteins at trigeminal ganglion and trigeminocervical complex, resulting in peripheral and central sensitization, respectively, and long-lasting changes [27 ]. Ayzenberg et al. used electrophysiologic studies to show that trigeminal nociception is affected in MOH [31]. Medication overuse can also stimulate the trigeminovascular system. One study demonstrated that rats who overused triptans had cutaneous tactile allodynia and increased CGRP levels [32]. Chronic ergot and acetaminophen administration can also facilitate trigeminal nociception [27, 28]. Opioids activate toll-like receptor-4 on glial cells, which release cytokines in response to CGRP, and promote a pro-inflammatory state [33]. Thus, medication overuse can induce peripheral and central sensitization via the trigeminal pain pathway [27 ]. Neurotransmitters play a key role in MOH, and MOH has been described as a serotonin deplete state [27 ]. Patients with MOH have lower levels of platelet serotonin, but serum serotonin levels increase after withdrawal of the offending drug [34, 35]. The serotonin system is closely tied with cortical spreading depression and the trigeminovascular system. Animals with low levels of serotonin are more susceptible to cortical spreading depression, have increased CGRP levels and have higher levels of c-fos expression in the trigeminocervical complex, a marker of trigeminal nociception [27 ]. Another mechanism by which low serotonin can promote MOH is by up-regulating pro-nociceptive 5- HT 2A receptors. Medication overuse with analgesics and acetaminophen can also increase the formation of 5-HT 2 and 5- HT 2A receptors, respectively [36 38]. Animals with longterm triptan use had changes in serotonin receptors and transporters in the periaqueductal grey and locus ceruleus [27 ]. Apart from serotonin abnormalities, MOH patients also have low cannabinoid levels. Cannabinoids exert an analgesic effect by inhibiting the trigeminovascular system, and their absence can contribute to the pathogenesis of MOH [27, 39]. Risk Factors Hagen et al. conducted a study to determine the risk factors for MOH. They found that smoking and having a sedentary lifestyle more than doubled MOH risk [40]. In addition, patients with chronic musculoskeletal complaints, gastrointestinal complaints and a hospital anxiety and depression scale score 11 had a fivefold increase in MOH [40]. MOH is linked to chronic musculoskeletal pains and coexists with anxiety, depression and obsessive compulsive disorder [41, 42]. Low socioeconomic status can also be associated with MOH [43]. Obesity is a risk factor for transformation to chronic migraine; however, it is unclear if there is a direct association between obesity and medication overuse headache. Taking certain medications increase the risk of developing MOH. Hagen et al. found that regular use of tranquilizers led to a fivefold increase in MOH [40]. Other offending medications include barbiturates, which increase MOH risk (OR 2.06) if used approximately 5 days per month or more [44]. It has a greater effect on females than males [45]possiblydue to differences in stress response and cortical excitability. Barbiturates are no longer available in Europe, but are still sold in the USA [8 ]. Opiates have a more pronounced effect on men and increase the risk of MOH (OR 1.98) after around 8 days of use per month [44, 45]. Triptans are more frequently seen in wealthy countries. They can lead to MOH progression in patients with 10 to 14 migraine days per month [8, 45]. It only took 1.7 years for triptan users to convert to MOH, as compared to 2.7 and 4.8 years in ergot and analgesic users, respectively [46]. Fortunately, patients who take triptans have shorter withdrawal headaches and use fewer rescue medications in the detoxification period [47]. NSAIDs were shown to have a protective effect from MOH in patients with less than 10 headache days per month, but this is controversial. Generally, high levels of NSAID use are associated with MOH [44]. Caffeine, a non-selective adenosine receptor antagonist, can also promote headache chronicity [48], possibly via modulating effect on neuronal, glial and vascular function. Clinical Presentation The most recent diagnostic criteria published in the ICHD-3 states that MOH is a headache occurring on 15 or more days per month in a patient with a pre-existing headache disorder. One or more acute/symptomatic medications are regularly used for over 3 months, and it is not better accounted for by another ICHD-3 diagnosis [6]. The most common headache diagnoses before MOH onset are migraines (65 %), tensiontype headaches (27 %), and mixed/other headaches (8 %) [8 ]. MOH can occur in headache prone patients who take analgesics for other reasons [21]. The transition from episodic headache to MOH is a gradual one. Patients experience an increase in headache frequency and severity. The headaches may vary in location, quality and intensity. However, it is the quantity, and not quality, of the headaches that makes the diagnosis [49]. Dousset et al. have created a screening tool based on the revised ICHD-2 criteria with a sensitivity of 95 % and a

4 509, Page 4 of 8 Curr Neurol Neurosci Rep (2015) 15:509 specificity of 80 % that can aid the practitioner in diagnosing probable MOH [50]. In this self questionnaire, patients are asked if they have headache 15 days per month, if treatment for attacks occur on 10 days per month for, and if this intake occurs on a regular basis [50]. MOH can be a challenging diagnosis to make because the headaches can change over time. Moreover, patients may suffer from different types of headaches and only report certain kinds to their physician [49]. Clinical presentations have such large variability because patients use different medications and do not withdraw from pharmacological agents in the same way [49]. To complicate matters, 90 % of MOH patients utilize more than one form of pain relief [8 ]. Using multiple classes of therapy is associated with medication dependence, continuous headaches, severe headaches and more phonophobia/photophobia compared to pure triptan users [51]. The headaches of MOH tend to occur in the morning, possibly due to overnight drug withdrawal or non-restorative sleep [8, 49]. Poor sleep is made worse by caffeine, but can improve by weaning the offending drug [49]. Neck pain is also a common symptom in MOH that usually improves with drug withdrawal [49]. Patients who overuse ergots are more likely to suffer from withdrawal headaches resembling tension headaches, but those taking triptans may experience withdrawal migraines [46]. Central sensitization can lead to expansion of the headache area and cutaneous allodynia [8 ]. Autonomic symptoms like rhinorrhea, lacrimation and postnasal drip as well as gastrointestinal symptoms can accompany the headaches [49]. MOH patients often find that they respond poorly to acute and preventative treatments and may have had unsuccessful trials in the past [49]. A lack of success with preventative agents may be due to insufficient dosing and duration of therapy. Diagnostic Criteria ICHD-III beta diagnostic criteria of MOH [6]: 1. Headache occurring on 15 days per month in a patient with a pre-existing headache disorder 2. Regular overuse for of one or more drugs that can be taken for acute and/or symptomatic treatment of headache [1] 3. Not better accounted for by another ICHD-3 diagnosis. According to the ICHD-III beta criteria, patients should be coded for one or more subtypes of MOH based on the specific medication(s) overused and the particular criteria for each medication. Patients who use multiple medications for acute or symptomatic treatment of headache can be diagnosed with MOH even though no individual drug is overused. MOH can be diagnosed if there is regular intake of opioids, ergotamine or triptans on 10 days per month for. Regular intake of multiple drug classes or combination analgesic use 10 days per month for and simple analgesic (Paracetamol, ASA, NSAIDs) on 15 days per month for can result in MOH (see Table 1). Treatment The treatment of MOH begins with patient education. Studies have demonstrated that patient education is beneficial in reducing MOH [52]. In simpler cases of MOH, where patients do not have psychiatric conditions and do not overuse opioids, conveying a strong message was as effective as an outpatient detoxification programme [53]. It is also important to work closely with the patient s family[54 ]. The next step is to determine whether the patient can be managed as an outpatient or whether they need to be closely monitored. Saper and Lake created a classification system that can be of use to triage these patients. Type 1 MOH refers to simpler cases of patients who do not have behavioural conditions and do not overuse opioids and barbiturates. Type 2 MOH patients are complex, and suffer from behavioural conditions, or chronically use opioids or barbiturates [54, 55]. Type 1 patients can at first be seen as outpatients with a clear rescue medication programme in place. Type 2 patients may need to be inpatients because they are more likely to have withdrawal symptoms, experience more pain and have sleep and emotional problems during the drug wean [54 ]. Some MOH patients may qualify for multidisciplinary programmes. These programmes involve a neurologist or pain specialist, primary care physician, psychologist, nursing staff and physiotherapist. Patients using drugs such as opioids, barbiturates and benzodiazepines need to be watched closely, and weaning requires special attention [49]. Research has shown that interdisciplinary management of MOH is effective. However, it is expensive and used for high-risk patients such as type 2 MOH patients or those who have relapsed previously [10, 49]. Once triage decisions have been made, the first step is to withdraw the offending drug. The European Federation of Neurological Societies (EFNS) guidelines from 2011 state that withdrawal therapy is the best treatment for MOH [56, 57]. To date, no studies have looked at differences between an abrupt versus a tapered withdrawal, but the consensus is that a faster withdrawal results in a rapid resolution [56]. For opioids, barbiturates and benzodiazepines, a tapered withdrawal is prudent to prevent significant withdrawal symptoms [56]. Some withdrawal symptoms that can occur after stopping the drug include headache worsening, anxiety, restlessness, nervousness, insomnia, tachycardia, hypotension, nausea and vomiting. They can last up to 4 weeks but normally occur for 2 to 10 days [56]. Seizures and hallucinations are rarely seen [10 ]. MOH outcomes did not differ when followed by a

5 Curr Neurol Neurosci Rep (2015) 15:509 Page 5 of 8, 509 Table 1 Medication overuse headache by drug class [6] Drug class Ergotamine Triptan ASA NSAIDs Acetaminophen/paracetamol Opioids Combination analgesics Multiple drug classes not individually overused: any of ergotamines, triptans, simple analgesics, NSAIDs, and/or opioids Duration of intake On 15 days per month for On 15 days per month for On 15 days per month for without overuse of a single drug class neurologist or a general practitioner in the detoxification period, so patients can be followed by their family physicians [58]. Next, a rescue plan should be put in place to minimize withdrawal symptoms. Drugs that can cause MOH should not be used at this time [54 ]. Many medications have been studied as bridge therapy in small trials. Pascual et al. concluded that naproxen, a long-acting NSAID, was beneficial as a rescue drug for MOH patients [59]. Other NSAIDs such as indomethacin and ketorolac can also be used without worsening MOH [54 ]. Tizanidine has been studied as an adjunct to a long-acting NSAID and was shown to be helpful [60]. Steroid medications were at once promising, but the current evidence is that they likely have minimal to no effect. One study revealed that patients on prednisone did not have fewer headache hours, but were able to use less rescue medication [61]. Another trial demonstrated no difference in patients on and off steroids, while a third small study found that prednisone could reduce the number of hours of moderate to severe headaches [62, 63]. Antiemetics work during drug weaning as well. Prochlorperazine was effective in one study [64]. Diphenhydramine and other neuroleptics such as chlorpromazine, promethazine and metoclopramide have also been used [54 ]. In more complex cases, infusions may need to be given and can be administered in an outpatient or inpatient setting [54 ]. One commonly used drug is dihydroergotamine (DHE). The regimen was originally studied by Raskin and now has been termed the Raskin protocol. In Raskin s trial, 55 patients, of whom 36 had MOH, were given IV DHE and metoclopramide every 8 h. The patients were compared to 54 patients, of whom 38 had MOH, and they were given diazepam instead. Of the patients treated with DHE, 49 were headache free in 48 h and 39 patients reported lasting benefits at 16 months [65]. Only seven patients were headache free in the diazepam group in 3 to 6 days. Thus, DHE is beneficial in the detoxification phase of MOH. However, they should not be used in patients with vascular diseases [49]. In patients who cannot take DHE, lidocaine infusions can be helpful. A retrospective study in patients with a history of analgesic abuse including narcotics showed that 90 % of MOH patients had an improvement in their headache, 97 % withdrew the overused drug and 70 % had sustained benefits at 6 months [66]. Another drug that can be used if DHE is ineffective is valproate. A small study with no control cohort reported that 80 % of MOH patients had headache improvement and that valproate was well tolerated [67]. Intravenous NSAIDs, antiemetics, hydration and magnesium are also helpful [54, 68]. Patients overusing opiates, barbiturates and tranquilizers may require long-acting opioids, phenobarbital and clonidine as a transition during detoxification [69 ]. Preventative therapies are often started when MOH treatment begins [54 ]. Choice of treatment depends on previously used drugs, patient preferences, the primary headache disorder, co-morbidities and side effects [56]. The usual migraine prevention medications like beta-blockers, calcium channel blockers, tricyclic antidepressants and anticonvulsants are suitable choices. They can be started at low doses and titrated up with time [54 ]. Topiramate has been studied and found to have beneficial effects in MOH patients [70]. In chronic migraine patients with and without medication overuse, topiramate decreased mean migraine days per month from 15.5 to 12 [70]. Topiramate is less effective in patients with medication overuse than those without it [54 ]. Therefore, the effect of topiramate is modest, but significant [71]. OnabotulinumtoxinA was originally studied in the PREEMPT 1 and 2 trials for chronic migraine, but many of the patients in the study also had medication overuse [72, 73]. A subgroup analysis of medication overuse patients reported benefit in reducing headache days as the primary endpoint. OnabotulinumtoxinA also decreased the frequency and severity of headaches [74]. However, it was not studied in patients who overused narcotics [72]. The COMOESTAS group showed that detoxification and prophylaxis of MOH patients decreased disability, depression and anxiety [75]. They have also created a treatment protocol based on the current evidence and performed a trial to test its efficacy (Table 2) [69 ]. The consensus protocol studied 376 MOH subjects in Europe and Latin America. At the conclusion of the trial, two thirds of patients no longer overused drugs and 46.5 % reverted back to episodic headaches. Both outpatient and inpatient detoxification programmes were effective, but the dropout rate was higher in the outpatients [69 ]. The protocol included the following steps:

6 509, Page 6 of 8 Curr Neurol Neurosci Rep (2015) 15:509 Prevention of relapse in MOH has not been well studied [69 ]. Withdrawal strategies and preventative therapies do not appear to affect prognosis or relapse rates [69 ]. Continual support in the form of education, patient monitoring through a headache diary and behavioural therapies are important [69 ]. Finally, increasing awareness in the general public should become the next goal. In a cohort of undergraduate students, 77 % were not aware that MOH existed. After learning about MOH, 80 % of the students stated they would reduce analgesic consumption and 83 % felt that medication bottles should warn against MOH [76]. Prognosis Patient motivation is key in the MOH treatment strategy [54 ]. Although withdrawal therapy is successful 72.4 % of the time at 1 to 6 months, the average relapse rate was 41 % at 4 years [10, 77]. Adding behavioural therapies can greatly reduce the relapse rate. Patients on medication alone had a 42.1 % relapse at 3 years, but when coupled with behavioural techniques, only 12.5 % reverted back to MOH [78]. One study showed that most patients relapse within the first year. The rates were 31, 41 and 45 % at 6 months, 1 year and 4 years, respectively [79]. Risk factors for conversion back to MOH include high baseline medication use, return to previously overused drugs, no improvement 2 months after withdrawal, smoking and alcohol use [8 ]. In terms of headache subtypes, migraine Table 2 Treatment protocol for MOH Use a headache diary [69 ] Step 1 Withdraw the overused medication (day 1) [69 ] Step 2A Detoxification and rescue therapy (day 1 to 7) [69 ] Antiemetics such as metoclopramide 10 mg IM or PO tid or equivalent (chlorpromazine, prochlorperazine, domperidone, levopromazine) Analgesics such as the following: Acetaminophen 1000 mg PO, PR or IVon demand or Naproxen 500 mg PO Maximum of 3 days within the first week. Patients should not use rescue therapy that is the same class of drug they previously overused Step 2B Preventative treatment (day 1 to 7), optional [69 ] Choose based on side effects, co-morbid conditions, previous therapeutic experiences from the following first line agents Beta-blockers propranolol mg/day, atenolol mg/ day, metoprolol mg/day Valproic acid mg/day Topiramate mg/day Flunarazine 5 10 mg/day Amitriptyline mg/day Candesartan 8 16 mg/day Step 3 Headache symptomatic medications (from day 8 and on) [69 ] Take headache medications at a maximum of 2 days per week. It should not be with the same class of drug previously overused Choice should be based on the patient s medical history, headache characteristics and past therapeutic experiences Modified table: permission from Tassorelli C, et al. Consensus protocol Cephalalgia patients tend to do better than tension-type or combined headache types in the long term [80]. Conclusion MOH is a common disorder worldwide that can greatly affect apatient s quality of life. In the past years, research has been done to elucidate the pathophysiology of MOH. Treatment trials have been small but promising. We can now shift our focus to devise primary prevention strategies and increase awareness of MOH so that patients will not become victims of their own headache therapies. Compliance with Ethics Guidelines Conflict of Interest Valerie Cheung and Farnaz Amoozegar declare that they have no conflict of interest. Esma Dilli has received speaker honorarium from Allergen and Tribune (Cambia). Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors. References Papers of particular interest, published recently, have been highlighted as: Of importance 1. Westergaard ML, Hansen EH, Glumer C, Olesen J, Jensen RH. Definitions of medication-overuse headache in population-based studies and their implications on prevalence estimates: a systematic review. Cephalalgia. Nov Peters GA, Horton BT. Headache: with special reference to the excessive use of ergotamine preparations and withdrawal effects. Proc Staff Meet Mayo Clin. 1951;26(9): Horton BT, Peters GA. Clinical manifestations of excessive use of ergotamine preparations and management of withdrawal effect: report of 52 cases. Headache. 1963;2: >Evers S, Marziniak M. Clinical features, pathophysiology, and treatment of medication-overuse headache. Lancet Neurol. 2010;9 (4): Classification and diagnostic criteria for headache disorders, cranial neuralgias and facial pain. Headache Classification Committee of the International Headache Society. Cephalalgia. 1988;8(Suppl 7): The International Classification of Headache Disorders, 3rd edition (beta version). Cephalalgia. 2013;33(9): Lanteri-Minet M, Duru G, Mudge M, Cottrell S. Quality of life impairment, disability and economic burden associated with chronic daily headache, focusing on chronic migraine with or without medication overuse: a systematic review. Cephalalgia. 2011;31(7): Da Silva AN, Lake 3rd AE. Clinical aspects of medication overuse headaches. Headache. 2014;54(1): Updated Clinical review of MOH.

7 Curr Neurol Neurosci Rep (2015) 15:509 Page 7 of 8, Colas R, Munoz P, Temprano R, Gomez C, Pascual J. Chronic daily headache with analgesic overuse: epidemiology and impact on quality of life. Neurology. 2004;62(8): Katsarava Z, Obermann M. Medication-overuse headache. Curr Opin Neurol. 2013;26(3): Broad updated review of MOH. 11. Ayzenberg I, Katsarava Z, Sborowski A, et al. The prevalence of primary headache disorders in Russia: a countrywide survey. Cephalalgia. 2012;32(5): Shahbeigi S, Fereshtehnejad SM, Mohammadi N, et al. Epidemiology of headaches in Tehran urban area: a populationbased cross-sectional study in district 8, year Neurol Sci. 2013;34(7): Linde M, Stovner LJ, Zwart JA, Hagen K. Time trends in the prevalence of headache disorders. The Nord-Trondelag Health Studies (HUNT 2 and HUNT 3). Cephalalgia. 2011;31(5): Dyb G, Holmen TL, Zwart JA. Analgesic overuse among adolescents with headache: the Head-HUNT-Youth Study. Neurology. 2006;66(2): Wang SJ, Fuh JL, Lu SR, Juang KD. Chronic daily headache in adolescents: prevalence, impact, and medication overuse. Neurology. 2006;66(2): Lu SR, Fuh JL, Chen WT, Juang KD, Wang SJ. Chronic daily headache in Taipei, Taiwan: prevalence, follow-up and outcome predictors. Cephalalgia. 2001;21(10): Wang SJ, Fuh JL, Lu SR, et al. Chronic daily headache in Chinese elderly: prevalence, risk factors, and biannual follow-up. Neurology. 2000;54(2): Meskunas CA, Tepper SJ, Rapoport AM, Sheftell FD, Bigal ME. Medications associated with probable medication overuse headache reported in a tertiary care headache center over a 15-year period. Headache. 2006;46(5): Cevoli S, Sancisi E, Grimaldi D, et al. Family history for chronic headache and drug overuse as a risk factor for headache chronification. Headache. 2009;49(3): Bahra A, Walsh M, Menon S, Goadsby PJ. Does chronic daily headache arise de novo in association with regular use of analgesics? Headache. 2003;43(3): Wilkinson SM, Becker WJ, Heine JA. Opiate use to control bowel motility may induce chronic daily headache in patients with migraine. Headache. 2001;41(3): Onaya T, Ishii M, Katoh H, et al. Predictive index for the onset of medication overuse headache in migraine patients. Neurol Sci. 2013;34(1): Saper JR, Hamel RL, Lake 3rd AE. Medication overuse headache (MOH) is a biobehavioural disorder. Cephalalgia. 2005;25(7): Ferraro S, Grazzi L, Muffatti R, et al. In medication-overuse headache, FMRI shows long-lasting dysfunction in midbrain areas. Headache. 2012;52(10): Fumal A, Laureys S, Di Clemente L, et al. Orbitofrontal cortex involvement in chronic analgesic-overuse headache evolving from episodic migraine. Brain. 2006;129(Pt 2): Coppola G, Schoenen J. Cortical excitability in chronic migraine. Curr Pain Headache Rep. 2012;16(1): Srikiatkhachorn A, le Grand SM, Supornsilpchai W, Storer RJ. Pathophysiology of medication overuse headache an update. Headache. 2014;54(1): Excellent review on pathophysiology of MOH. 28. Supornsilpchai W, le Grand SM, Srikiatkhachorn A. Cortical hyperexcitability and mechanism of medication-overuse headache. Cephalalgia. 2010;30(9): Coppola G, Curra A, Di Lorenzo C, et al. Abnormal cortical responses to somatosensory stimulation in medication-overuse headache. BMC Neurol. 2010;10: Ferraro S, Grazzi L, Mandelli ML, et al. Pain processing in medication overuse headache: a functional magnetic resonance imaging (fmri) study. Pain Med. 2012;13(2): Ayzenberg I, Obermann M, Nyhuis P, et al. Central sensitization of the trigeminal and somatic nociceptive systems in medication overuse headache mainly involves cerebral supraspinal structures. Cephalalgia. 2006;26(9): De Felice M, Ossipov MH, Wang R, et al. Triptan-induced latent sensitization: a possible basis for medication overuse headache. Ann Neurol. 2010;67(3): Johnson JL, Hutchinson MR, Williams DB, Rolan P. Medicationoveruse headache and opioid-induced hyperalgesia: a review of mechanisms, a neuroimmune hypothesis and a novel approach to treatment. Cephalalgia. 2013;33(1): Srikiatkhachorn A, Anthony M. Platelet serotonin in patients with analgesic-induced headache. Cephalalgia. 1996;16(6): Hering R, Glover V, Pattichis K, Catarci T, Steiner TJ. 5HT in migraine patients with medication-induced headache. Cephalalgia. 1993;13(6): Srikiatkhachorn A, Anthony M. Serotonin receptor adaptation in patients with analgesic-induced headache. Cephalalgia. 1996;16(6): Ayzenberg I, Obermann M, Leineweber K, et al. Increased activity of serotonin uptake in platelets in medication overuse headache following regular intake of analgesics and triptans. J Headache Pain. 2008;9(2): Supornsilpchai W, le Grand SM, Srikiatkhachorn A. Involvement of pro-nociceptive 5-HT2A receptor in the pathogenesis of medication-overuse headache. Headache. 2010;50(2): Rossi C, Pini LA, Cupini ML, Calabresi P, Sarchielli P. Endocannabinoids in platelets of chronic migraine patients and medication-overuse headache patients: relation with serotonin levels. Eur J Clin Pharmacol. 2008;64(1): Hagen K, Linde M, Steiner TJ, Stovner LJ, Zwart JA. Risk factors for medication-overuse headache: an 11-year follow-up study. The Nord-Trondelag Health Studies. Pain. 2012;153(1): Curone M, Tullo V, Savino M, Proietti-Cecchini A, Bussone G, D Amico D. Outcome of patients with chronic migraine with medication overuse and depression after duloxetine: influence of coexisting obsessive compulsive disorder. Neurol Sci. 2013;34 Suppl 1:S Hagen K, Linde M, Steiner TJ, Zwart JA, Stovner LJ. The bidirectional relationship between headache and chronic musculoskeletal complaints: an 11-year follow-up in the Nord-Trondelag Health Study (HUNT). Eur J Neurol. 2012;19(11): Hagen K, Vatten L, Stovner LJ, Zwart JA, Krokstad S, Bovim G. Low socio-economic status is associated with increased risk of frequent headache: a prospective study of adults in Norway. Cephalalgia. 2002;22(8): Bigal ME, Serrano D, Buse D, Scher A, Stewart WF, Lipton RB. Acute migraine medications and evolution from episodic to chronic migraine: a longitudinal population-based study. Headache. 2008;48(8): Bigal ME, Lipton RB. Excessive acute migraine medication use and migraine progression. Neurology. 2008;71(22): Limmroth V, Katsarava Z, Fritsche G, Przywara S, Diener HC. Features of medication overuse headache following overuse of different acute headache drugs. Neurology. 2002;59(7): Katsarava Z, Fritsche G, Muessig M, Diener HC, Limmroth V. Clinical features of withdrawal headache following overuse of triptans and other headache drugs. Neurology. 2001;57(9): Scher AI, Stewart WF, Lipton RB. Caffeine as a risk factor for chronic daily headache: a population-based study. Neurology. 2004;63(11): Tepper SJ. Medication-overuse headache. Continuum (Minneap Minn). 2012;18(4): Dousset V, Maud M, Legoff M, et al. Probable medications overuse headaches: validation of a brief easy-to-use screening tool in a headache centre. J Headache Pain. 2013;14:81.

8 509, Page 8 of 8 Curr Neurol Neurosci Rep (2015) 15: Creac h C, Radat F, Mick G, et al. One or several types of triptan overuse headaches? Headache. 2009;49(4): Grande RB, Aaseth K, Benth JS, Lundqvist C, Russell MB. Reduction in medication-overuse headache after short information. The Akershus study of chronic headache. Eur J Neurol. 2011;18(1): Rossi P, Di Lorenzo C, Faroni J, Cesarino F, Nappi G. Advice alone vs. structured detoxification programmes for medication overuse headache: a prospective, randomized, open-label trial in transformed migraine patients with low medical needs. Cephalalgia. 2006;26(9): Saper JR, Da Silva AN. Medication overuse headache: history, features, prevention and management strategies. CNS Drugs. 2013;27(11): Updated review on MOH including prevention and treatment approach. 55. Saper JR, Lake 3rd AE. Medication overuse headache: type I and type II. Cephalalgia. 2006;26(10): Evers S, Jensen R. Treatment of medication overuse headache guideline of the EFNS headache panel. Eur J Neurol. 2011;18(9): Zeeberg P, Olesen J, Jensen R. Discontinuation of medication overuse in headache patients: recovery of therapeutic responsiveness. Cephalalgia. 2006;26(10): Boe MG, Salvesen R, Mygland A. Chronic daily headache with medication overuse: predictors of outcome 1 year after withdrawal therapy. Eur J Neurol. 2009;16(6): Pascual J, Berciano J. [Daily chronic headache in patients with migraine induced by abuse of ergotamine-analgesics: response due to a protocol of outpatient treatment]. Neurologia. 1993;8(7): Smith TR. Low-dose tizanidine with nonsteroidal antiinflammatory drugs for detoxification from analgesic rebound headache. Headache. 2002;42(3): Rabe K, Pageler L, Gaul C, et al. Prednisone for the treatment of withdrawal headache in patients with medication overuse headache: a randomized, double-blind, placebo-controlled study. Cephalalgia. 2013;33(3): Boe MG, Mygland A, Salvesen R. Prednisolone does not reduce withdrawal headache: a randomized, double-blind study. Neurology. 2007;69(1): Pageler L, Katsarava Z, Diener HC, Limmroth V. Prednisone vs. placebo in withdrawal therapy following medication overuse headache. Cephalalgia. 2008;28(2): Lu SR, Fuh JL, Juang KD, Wang SJ. Repetitive intravenous prochlorperazine treatment of patients with refractory chronic daily headache. Headache. 2000;40(9): Raskin NH. Repetitive intravenous dihydroergotamine as therapy for intractable migraine. Neurology. 1986;36(7): Williams DR, Stark RJ. Intravenous lignocaine (lidocaine) infusion for the treatment of chronic daily headache with substantial medication overuse. Cephalalgia. 2003;23(10): Schwartz TH, Karpitskiy VV, Sohn RS. Intravenous valproate sodium in the treatment of daily headache. Headache. 2002;42(6): Trucco M, Meineri P, Ruiz L, Gionco M. Medication overuse headache: withdrawal and prophylactic therapeutic regimen. Headache. 2010;50(6): Tassorelli C, Jensen R, Allena M, et al. A consensus protocol for the management of medication-overuse headache: evaluation in a multicentric, multinational study. Cephalalgia. Feb Protocol for managing MOH. 70. Diener HC, Dodick DW, Goadsby PJ, et al. Utility of topiramate for the treatment of patients with chronic migraine in the presence or absence of acute medication overuse. Cephalalgia. 2009;29(10): Russell MB, Lundqvist C. Prevention and management of medication overuse headache. Curr Opin Neurol. 2012;25(3): Aurora SK, Dodick DW, Turkel CC, et al. OnabotulinumtoxinA for treatment of chronic migraine: results from the double-blind, randomized, placebo-controlled phase of the PREEMPT 1 trial. Cephalalgia. 2010;30(7): Diener HC, Dodick DW, Aurora SK, et al. OnabotulinumtoxinA for treatment of chronic migraine: results from the double-blind, randomized, placebo-controlled phase of the PREEMPT 2 trial. Cephalalgia. 2010;30(7): Silberstein SD, Blumenfeld AM, Cady RK, et al. OnabotulinumtoxinA for treatment of chronic migraine: PREEMPT 24-week pooled subgroup analysis of patients who had acute headache medication overuse at baseline. J Neurol Sci. 2013;331(1 2): Bendtsen L, Munksgaard S, Tassorelli C, et al. Disability, anxiety and depression associated with medication-overuse headache can be considerably reduced by detoxification and prophylactic treatment. Results from a multicentre, multinational study (COMOESTAS project). Cephalalgia. Dec Lai JT, Dereix JD, Ganepola RP, et al. Should we educate about the risks of medication overuse headache? J Headache Pain. 2014;15: Hagen K, Albretsen C, Vilming ST, et al. A 4-year follow-up of patients with medication-overuse headache previously included in a randomized multicentre study. J Headache Pain. 2011;12(3): Grazzi L, Andrasik F, D Amico D, et al. Behavioral and pharmacologic treatment of transformed migraine with analgesic overuse: outcome at 3 years. Headache. 2002;42(6): Katsarava Z, Muessig M, Dzagnidze A, Fritsche G, Diener HC, Limmroth V. Medication overuse headache: rates and predictors for relapse in a 4-year prospective study. Cephalalgia. 2005;25(1): Schnider P, Aull S, Baumgartner C, et al. Long-term outcome of patients with headache and drug abuse after inpatient withdrawal: five-year follow-up. Cephalalgia. 1996;16(7): discussion 461.