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The pathogenesis of medication overuse headache is unclear. Clinical and preclinical studies have consistently demonstrated increased excitability of neurons in the cerebral cortex and trigeminal system after medication overuse. Cortical hyperexcitability may facilitate the development of cortical spreading depression, while increased excitability of trigeminal neurons may facilitate the process of peripheral and central sensitization. These changes may be secondary to the derangement of central, probably serotonin (5-HT)-, and perhaps endocannabinoid-dependent or other, modulating systems. Increased expression of excitatory cortical 5-HT2A receptors may increase the susceptibility to developing cortical spreading depression, an analog of migraine aura. A reduction of diffuse noxious inhibitory controls may facilitate the process of central sensitization, activate the nociceptive facilitating system, or promote similar molecular mechanisms to those involved in kindling. Low 5-HT levels also increase the expression and release of calcitonin gene-related peptide from the trigeminal ganglion and sensitize trigeminal nociceptors. Thus, derangement of central modulation of the trigeminal system as a result of chronic medication use may increase sensitivity to pain perception and foster or reinforce medication overuse headache., (© 2013 American Headache Society.)

Cranial or cervical vascular disease is commonly associated with headaches. The descriptions may range from a thunderclap onset of a subarachnoid hemorrhage to a phenotype similar to tension type headache. Occasionally, this may be the sole manifestation of a potentially serious underlying disorder like vasculitis. A high index of clinical suspicion is necessary to diagnose the disorder. Prompt recognition and treatment is usually needed for many conditions to avoid permanent sequelae that result in disability. Treatments for many conditions remain challenging and are frequently controversial due to paucity of well controlled studies. This is a review of the recent advances that have been made in the diagnosis or management of these secondary headaches.

Familiarity with the risks associated with medication overuse and the importance of headache prophylaxis is key to easing your patient's pain.

“An ounce of prevention is worth a pound of cure” in the management of MOH. Prevention of transformation of primary headache types to their chronic counterparts is necessary to prevent this most troubling transformation. Strict attention to what patients are telling you (and often times not telling you) about their episodic headaches will enable pharmacologic and nonpharmacologic measures to avoid that transformation to chronic daily headache, so often associated with MOH. Once MOH becomes manifest, withdrawal of the overused drug is mandatory; otherwise experience tells us the pattern of overuse will only be perpetuated and no measure will help alleviate the headache. At the same time, as detoxification takes place, measures to ensure that relapse will not take place should begin. These efforts include prophylactic pharmacologic measures as well as psychological support, education, and surveillance to prevent relapses. The rate of relapse is unfortunately high, but these general and specific measures enumerated above will add greatly to the chances of success., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Background: Medication overuse headache (MOH) is a disabling health problem. Convincing evidence attributes a pathophysiologic role to central sensitization. By recording somatosensory evoked potentials (SSEPs) in patients with MOH, we observed increased sensitization and deficient habituation to repetitive sensory stimuli consistent with drug overuse. The renin-angiotensin system in the brain seems to play a relevant role in neural plasticity and dependence behavior. We therefore sought differences in SSEP sensitization and habituation in patients with MOH who underwent angiotensin converting enzyme (ACE) I/D polymorphism analysis., Methods: We recorded median-nerve SSEPs (two blocks of 100 sweeps) in 43 patients with MOH. We measured N20-P25 amplitudes, and assessed sensitization using the first block amplitudes, and habituation using amplitude changes between the two sequential blocks. According to their genotype, subjects were divided into three groups: "D/D", "D/I" and "I/I" carriers., Results: The habituation slope of the two SSEP block amplitudes was significantly increased in the D/D subgroup (n = 16) with respect to that of the I/I subgroup (n = 6), with the D/I subgroup (n = 21) falling in between. In D/D carriers, the habituation slope correlated positively with the duration of the overuse headache, and the first SSEP block amplitudes, a measure of sensitization, increased in strict relationship with the type of overused medication in the MOH patients overall and in the D/D subgroup; this was not so in the D/I and I/I subgroups., Conclusion: In patients with MOH, the homozygote D/D ACE polymorphism influences habituation and sensitization to repeated sensory stimuli in strict relationship with medication overuse. We suggest that angiotensin peptides influence neuronal mechanisms of plasticity by interacting with central monoaminergic synaptic transmission.

Objective: Orbitofrontal cortex (OFC) dysfunction and poor decision making have been described in patients with chronic migraine and medication overuse. These neurobiological underpinnings might explain dependency-like behaviors often described in this condition, such as loss of control over painkillers, high rates of relapse after detoxification, and compromised social functioning. We investigate whether the OFC impairment was a persistent trait in migraine, independent of clinical and affective features, a dynamic result of the need to cope with the increased pain and disability, or a temporary consequence of medication overuse., Methods: For this purpose, we compared 40 chronic migraineurs with medication overuse, 40 episodic migraineurs, and 40 matched healthy controls. The examination consisted of a clinical interview, Anxiety and Depression Hamilton Scales, Severity of Dependence Scale, and Migraine Disability Assessment questionnaire. A neuropsychological assessment of orbitofrontal function was made through the Iowa Gambling Task (IGT). Chronic migraineurs with medication overuse were followed for a year after detoxification., Results: We found an impaired decision-making performance among chronic and episodic migraineurs that seems independent of the patients' clinical and affective status. Contrary to the psychiatric and clinical improvement shown 1 year after the detox, CM patients exhibited a persistent IGT deficit. No significant differences in OFC functioning were found between the CM patients who relapsed into medication overuse after detox and those who did not., Conclusions: The present findings suggest the presence of a persistent OFC dysfunction in migraine as a psychobiologic trait that is not influenced by the presence of medication overuse, the clinical severity of the disease, or the patient's affective status. Further studies are needed to elucidate the etiopathological role of OFC in migraine and medication overuse., (© 2012 American Headache Society.)

Objective: The primary aim of our study was to evaluate if a group of medication-overuse headache (MOH) patients present dysfunctions in the mesocorticolimbic dopamine circuit. The secondary aim was to disentangle the role of the medication overuse and of the acute/chronic headache in determining these alterations and to investigate their persistence., Background: Several researches have suggested that MOH may belong to the spectrum of addictive behavior. Preclinical models and neuroimaging studies have consistently demonstrated that in addiction, critical long-lasting alterations occur in the mesocorticolimbic dopamine circuit. If MOH shares some neurophysiological features with addiction, long-lasting functional alterations of the mesocorticolimbic dopamine system related to medication overuse should be present., Methods: We collected functional magnetic resonance imaging data during the execution of a decision-making under risk paradigm in 8 MOH patients immediately after beginning medication withdrawal, in 8 detoxified MOH patients at 6 months after beginning medication withdrawal, in 8 chronic migraine patients, and in 8 control subjects., Results: Our results revealed that MOH patients present: (1) reduced task-related activity in the substantia nigra/ventral tegmental area complex and increased activity in the ventromedial prefrontal cortex, when compared with controls; (2) reduced activity in the substantia nigra/ventral tegmental area complex, when compared with chronic migraine patients; (3) increased activity in the ventromedial prefrontal cortex, when compared with detoxified MOH patients., Conclusion: Our study showed that MOH patients present dysfunctions in the mesocorticolimbic dopamine circuit, in particular in the ventromedial prefrontal cortex and in the substantia nigra/ventral tegmental area complex. The ventromedial prefrontal cortex dysfunctions seem to be reversible and attributable to the acute/chronic headache, whereas the substantia nigra/ventral tegmental area complex dysfunctions are persistent and possibly related to medication overuse. These dysfunctions might be the expression of long-lasting neuroadaptations related to the overuse of medications and/or a pre-existing neurophysiological condition leading to vulnerability to medication overuse. The observed persistent dysfunctions in the midbrain dopamine suggest that MOH may share some neurophysiological features with addiction., (© 2012 American Headache Society.)

Purpose of Review: Medication-overuse headache (MOH) is a chronic daily headache in which acute medications used at high frequency cause transformation to headache occurring 15 or more days per month for 4 or more hours per day if left untreated. MOH is a form of US Food and Drug Administration-defined chronic migraine. This review will describe (1) MOH clinical features and diagnosis, (2) pathophysiology and structural and functional MOH brain changes, and (3) prevention and treatment of MOH., Recent Findings: MOH causes structural and functional brain changes. Any butalbital or opioid use increases the risk of transforming episodic into chronic migraine (sometimes referred to as chronification). The American Migraine Prevalence and Prevention Study demonstrated that transformation is most likely to occur with 5 days of butalbital use per month, 8 days of opioid use per month, 10 days of triptan or combination analgesic use per month, and 10 to 15 days of nonsteroidal anti-inflammatory use per month. Acute migraine treatment should be limited to 2 or fewer days per week, and opioids and butalbital should be avoided.Treatment of MOH consists of combining prophylaxis, 100% wean of overused acute medications, and provision of new acute medications, strictly limiting use to 2 or fewer days per week. Wean can be done slowly in an outpatient setting or it can be done abruptly, sometimes requiring hospitalization with medicine bridges., Summary: MOH development is linked to baseline frequency of headache days per month, acute medication class ingested, frequency of acute medications ingested, and other risk factors. Using less effective or nonspecific medication for severe migraine results in inadequate treatment response, with redosing and attack prolongation, frequently leading to chronification. Use of any barbiturates or opioids increases the transformation likelihood.Patients with MOH can usually be effectively treated. The first step is 100% wean, followed by establishing preventive medications such as onabotulinumtoxinA or daily prophylaxis and providing acute treatment for severe migraine 2 or fewer days per week. Slow wean or quick termination of rebound medications can be accomplished for most patients on an outpatient basis, but some more difficult problems may need referral for multidisciplinary day hospital or inpatient treatments.

Patients with chronic migraine developing medication-overuse headache (MOH) show dependency-like behaviors such as loss of control over analgesics despite adverse consequences on headaches, high rates of relapse after withdrawal from symptomatic medications, and compromised social functioning. Neuroimaging research suggests a common pathophysiology between substance-use disorders and MOH, which involves functional alterations in fronto-striatal networks, particularly in the orbitofrontal region of prefrontal cortex. These findings could explain the impaired decision-making observed in substance-use disorders. We hypothesize that MOH could share fronto-striatal circuit dysfunction and relative decision-making deficit with addiction. We further examine whether this deficit is a persistent cognitive trait or a reversible consequence of medication overuse. This study shows a dataset of 50 patients with MOH before the detoxification. All patients underwent a complete neurological and psychiatric examination. Psychiatric examination consisted of a clinical interview, Structured Clinical Interview for DSM-IV TR Axis II Personality Disorders, Anxiety and Depression Hamilton Scales, Severity of Dependence Scale. The neurological examination included the migraine disability assessment questionnaire. Neuropsychological assessment of fronto-striatal circuits was investigated using the Iowa gambling task (IGT). Twenty patients monitored for any relapse into medication overuse had 12 months of follow-up. Our sample, characterized by high rates of disability and dependency-like behaviors, exhibited a deficit in IGT performance, indicating an overall impairment in decision-making. All the 20 patients showed neurological and psychiatric improvement at 12-month follow-up, notwithstanding the overuse relapse, but a persistent IGT deficit was found. To our knowledge this is the first study that assesses this cognitive function in patients with MOH. Medication-overuse headache seems to share a persistent decision-making deficit with substance abuse that confirms the orbitofrontal cortex hypometabolism described in literature from a neuropsychological perspective. Looking at these shared neurocognitive features, our results suggest that MOH could belong to the addiction spectrum. Fronto-striatal dysfunction could be a premorbid psychobiological condition of vulnerability explaining the clinical onset of medication overuse and recurrent relapses. We propose that IGT could be used to identify chronic migraine patients with higher risk for medication overuse and relapse.

Temporomandibular disorders are among the potential comorbidities of migraine, and recent reports showed that they may have a role in promoting its progression into chronic migraine (CM). In order to clarify the possible role of neuromuscular components of the stomatognathic system in patients with CM, we studied 18 patients admitted as inpatients at our Headache Unit to undergo a withdrawal protocol for medication overuse, who underwent orthosis, after clinical and instrumental gnathological evaluation. They were subsequently evaluated after 6 months. The values of electromyographic parameters as well as of pain outcomes showed a significant decrease after orthosis. The implementation of gnathological and neuromuscular concepts can have a relevant role in the management of CM patients, in the contest of a multidisciplinary approach.

Recent animal experiments have shown that chronic medication exposure profoundly affects the function of several areas in the nervous system related to headache pathogenesis. These changes include upregulation of calcitonin gene-related peptide, substance P, and nitric oxide synthase in trigeminal ganglia; expansion of receptive field and decreased nociceptive threshold of central trigeminal neurons; decrease in diffuse noxious inhibitory control; and increased susceptibility to develop cortical spreading depression (CSD). These changes indicate an increase in excitability of cortical and trigeminal neurons. The neuronal hyperexcitability may be the result of derangement of a central, possibly serotonin (5-HT)-dependent, modulating control system. Experiments with animals with low 5-HT showed that the processes of CSD and trigeminal nociception are enhanced in this condition. Derangement in the central 5-HT-dependent modulating system as a result of chronic medication use may underlie the chronification of headache as observed in patients with medication-overuse headache.

Objective: The primary aim was to investigate functional differences between medication overuse headache (MOH) patients and controls with the purpose of evaluating the presence of a global alteration in the processing of noxious stimuli throughout the pain matrix. The secondary aim was to investigate whether activations in MOH patients normalize after medication withdrawal, which would suggest a possible role of the pain matrix in headache chronification., Design: Functional magnetic resonance imaging was performed during painful mechanical stimulation in nine female patients with MOH immediately and at 6 months after beginning medication withdrawal, and in nine control participants., Results: Compared with controls, immediately after beginning withdrawal, the MOH patients showed reduced pain-related activity across the primary somatosensory cortex, inferior parietal lobule, and supramarginal gyrus, as well as in regions of the lateral pathway of the pain matrix. At 6 months, these differences were no longer detectable., Conclusion: Our findings suggest that significant functional changes occur in the lateral pain pathway in MOH patients. These could result from different processes: 1) cortical down-regulation aimed at reducing painful input to the cortex; 2) activity-dependent plasticity induced by excessive painful input during migraine attacks; and 3) direct effect of medication overuse. At 6 months after withdrawal, activity in these regions normalized, suggesting that no irreversible changes occur due to medication overuse., (Wiley Periodicals, Inc.)

A proportion of episodic migraine patients experiences a progressive increase in attack frequency leading to chronic migraine (CM). The most frequent external factor that leads to headache chronification is medication overuse. The neurobiological bases of headache chronification and of the vicious circle of medication overconsumption are not completely elucidated. More recently, the same neurophysiological methods used to study episodic migraine were applied to CM and medication-overuse headache (MOH). Studies of cortical responsivity tend overall to indicate an increase in excitability, in particular of somatosensory and visual cortices, reflected by increased amplitude of evoked responses, decreased activity of inhibitory cortical interneurons reflected in the smaller magnetic suppression of perceptual accuracy, and, at least for visual responses, an increase in habituation. In MOH, overconsumption of triptans or NSAIDs influences cortical excitability differently. Generalized central sensitization is suggested to play an important role in the pathophysiology of headache chronification.

In the field of so-called chronic daily headache, it is not easy for migraine that worsens progressively until it becomes daily or almost daily to find a precise and universally recognized place within the current international headache classification systems. In line with the 2006 revision of the second edition of the International Classification of Headache Disorders (ICHD-2R), the current prevailing opinion is that this headache type should be named chronic migraine (CM) and be characterized by the presence of at least 15 days of headache per month for at least 3 consecutive months, with headache having the same clinical features of migraine without aura for at least 8 of those 15 days. Based on much evidence, though, a CM with the above characteristics appears to be a heterogeneous entity and the obvious risk is that its definition may be extended to include a variety of different clinical entities. A proposal is advanced to consider CM a subtype of migraine without aura that is characterized by a high frequency of attacks (10-20 days of headache per month for at least 3 months) and is distinct from transformed migraine (TM), which in turn should be included in the classification as a complication of migraine. Therefore, CM should be removed from its current coding position in the ICHD-2 and be replaced by TM, which has more restrictive diagnostic criteria (at least 20 days of headache per month for at least 1 year, with no more than 5 consecutive days free of symptoms; same clinical features of migraine without aura for at least 10 of those 20 days).

Chronic migraine (CM) represents migraine natural evolution from its episodic form. It is realized through a chronicization phase that may require months or years and varies from patient to patient. The transition to more frequent attacks pattern is influenced by lifestyle, life events, comorbid conditions and personal genetic terrain, and it often leads to acute drugs overuse. Medication overuse headache (MOH) may complicate every type of headache and all the drugs employed for headache treatment can cause MOH. The first step in the management of CM complicated by medication overuse must be the withdrawal of the overused drugs and a detoxification treatment. The goal is not only to detoxify the patient and stop the chronic headache but also to improve responsiveness to acute or prophylactic drugs. Different methods have been suggested: gradual or abrupt withdrawal; home treatment, hospitalization, or a day-hospital setting; re-prophylaxes performed immediately or at the end of the wash-out period. Up to now, only topiramate and local injection of onabotulinumtoxinA have shown efficacy as therapeutic agents for re-prophylaxis after detoxification in patients with CM with and without medication overuse. Although the two treatments showed similar efficacy, onabotulinumtoxinA is associated with a better adverse events profile. Recently, the Phase III Research Evaluating Migraine Prophylaxis Therapy (PREEMPT) clinical program proved that patients with CM, even those with MOH, are the ones most likely to benefit from onabotulinumtoxinA treatment. Furthermore, it provided an injection paradigm that can be used as a guide for a correct administration of onabotulinumtoxinA.

The aim of this study was to investigate, by means of transcranial Doppler ultrasound (TCD), cerebrovascular reactivity during the Valsalva maneuver (VM) during the headache-free interval in patients with migraine (M), migraine plus tension-type headache (M+TTH), and migraine plus medication overuse headache (M+MOH). A total of 114 patients (n=60 M, n=38 M+TTH, n=16 M+MOH) and n=60 controls were investigated; diagnoses were made according to the International Headache Society criteria. All subjects underwent TCD monitoring and, simultaneously, non-invasive assessment of arterial blood pressure and end-tidal CO2. Two indices were determined: the cerebrovascular Valsalva ratio (CVR) was calculated as the maximum end-diastolic flow velocity acceleration during the late straining phase of the VM [cm/s2] and the centroperipheral Valsalva ratio (CPVR) was defined as the quotient of CVR to the concomitant arterial blood pressure acceleration [cm/mmHg x s]. The dynamic cerebrovascular autoregulatory response to the VM, measured as CVR, was increased in patients with M and M+TTH compared to age-matched healthy subjects. By contrast, CPVR (i.e. the quotient of the cerebrovascular to the peripheral autonomic response), was increased in M patients compared to healthy subjects and all other headache conditions tested. Cerebrovascular autoregulatory response during the VM was increased in M patients compared to age-matched normal healthy subjects, indicating a disturbed autonomic control of cerebral vasoreactivity. The CPVR seems to be a sensitive parameter for distinguishing between M patients and M+TTH or M+MOH patients.

Headache attributable to nonvascular intracranial disorder is a basket of multiple, partly complex, and very diverse idiopathic or secondary disorders. By definition, the headache has to occur in a close temporal relationship to the intracranial disorder. Some of these headache disorders are caused by high or low cerebrospinal fluid pressure; noninfectious inflammatory diseases such as neurosarcoidosis, aseptic (noninfectious) meningitis, and lymphocytic hypophysitis; or intracranial neoplasm. Other nonvascular headaches, including hemicrania epileptica and postseizure headache, Chiari malformation type I, and the syndrome of transient headache and neurological deficits with cerebrospinal fluid lymphocytosis, are attributed to hypothalamic or pituitary hyper- or hyposecretion, intrathecal injection, or epileptic seizures. The clinical presentation of all these disorders can be diverse and often mimics the characteristics of primary headaches, which may delay the diagnosis.

Cervicogenic headache (CeH) is a relatively common syndrome. The paroxysmal and rather intense head pain usually is unilateral, spreading from the back of the head to the frontal and temporal regions, and triggered by certain movements or sustained provocative head positions. Digital pressure over triggering areas at the upper nuchal area reproduces the spontaneous pain pattern. Available clinical criteria differentiate this picture from other headache disorders, although superposition may be present in some cases. The neck is involved with other pain disorders apart from CeH. Migraine may be induced by cervical trigger factors in some cases, and whiplash lesions produce CeH-like symptoms as well as others. Occipital neuralgia refers to pain restricted to the distribution of the affected nerve and should not be mistaken as CeH. There is no definite, universal treatment for CeH yet. Options include physical therapy, preventive medicines, anesthetic blocks, denervation procedures, and surgery. The treatment choice must be performed on individual basis.

Introduction: Some data in the current medical literature suggests a link between medication overuse headache (MOH) and addictive behaviors. We present here a review of the clinical and biological data highlighting the role of addictive behaviors in MOH., Results: One third to one half of MOH patients will relapse in their overuse within five years following withdrawal of the offending medication. Some studies have shown that two thirds of MOH patients fulfil DSM-IV criteria for dependence concerning their use of acute headache medication. Moreover, there is a co-morbidity between substance related disorders and MOH and some data suggest a familial co-transmission between MOH and substancerelated disorders. In a prospective study, the use of acute headache medication containing psychoactive substances like opiate derivates increase the risk of transformation from an episodic headache to MOH suggesting the role of conditioning factors among other psychological variables as catastrophizing and a low self-efficacy. Finally, data from the neuroimagery, biology and genetic fields suggest the presence of common pathophysiological features between MOH and addiction. In particular, a study found a hypometabolism in the prefrontal cortex of MOH patients, not recovering after withdrawal, such abnormality being described in addicted patients and suggesting an inability of the prefrontal cortex to inhibit craving., Perspectives: All these data suggest that with MOH we face two sets of patients. The first one, in which medication overuse is mainly due to the worsening of the headache course, with minimal psychiatric contribution ; the second one, in which addictive behavior can play a major role. In the first case, education can simply lead to a significant reduction of medication intake, whereas in the second case a pluridisciplinary follow-up must be proposed before, during and after acute headache detoxification., Conclusion: A pluridisciplinary approach is the only way to reduce the relapse rate which remains too high in MOH., (Copyright © 2011 Elsevier Masson SAS. All rights reserved.)

The aim of this study was to analyze cutaneous pain threshold (CPT) during the interictal phase in headache patients, and the relationships between headache frequency and analgesic use. A consecutive series of 98 headache patients and 26 sex- and age-balanced controls were evaluated. Acute allodynia (AA) was assessed by Jakubowski questionnaire, and interictal allodynia (IA) by a skin test with calibrated monofilaments. AA is widely known as a symptom more present in migraine than in TTH spectrum: in our study this was confirmed only in cases of episodic attacks. When headache index rises towards chronicization, the prevalence of AA increases in both headache spectrums (χ (2) 13.55; p < 0.01). AA was associated with IA only in cases of chronic headache. When headache becomes chronic, mostly in presence of medication overuse, interictal CPT decreases and IA prevalence increases (χ (2) 20.44; p < 0.01), with closer association than AA. In MOH patients there were no significant differences depending on the diagnosis of starting headache (migraine or tension type headache) and, in both groups, we found the overuse of analgesics plays an important role: intake of more than one daily drug dramatically reduces the CPT (p < 0.05). Thus, when acute allodynia increases frequency, worsens or appears for the first time in patients with a long-standing history of chronic headache, it could reasonably suggest that the reduction of CPT had started, without using a specific practical skin test but simply by questioning clinical headache history. In conclusion, these results indicate that the role of medication overuse is more important than chronicization in lowering CPT, and suggest that prolonged periods of medication overuse can interfere with pain perception by a reduction of the pain threshold that facilitates the onset of every new attack leading to chronicization.

Introduction: Medication overuse headache (MOH) is a clinical concern in the management of migraine headache. MOH arises from the frequent use of medications used for the treatment of a primary headache. Medications that can cause MOH include opioid analgesics as well as formulations designed for the treatment of migraine, such as triptans, ergot alkaloids, or drug combinations that include caffeine and barbiturates., Literature Review: Gathering evidence indicates that migraine patients are more susceptible to development of MOH, and that prolonged use of these medications increases the prognosis for development of chronic migraine, leading to the suggestion that similar underlying mechanisms may drive both migraine headache and MOH. In this review, we examine the link between several mechanisms that have been linked to migraine headache and a potential role in MOH. For example, cortical spreading depression (CSD), associated with migraine development, is increased in frequency with prolonged use of topiramate or paracetamol., Conclusions: Increased CGRP levels in the blood have been linked to migraine and elevated CGRP can be casued by prolonged sumatriptan exposure. Possible mechanisms that may be common to both migraine and MOH include increased endogenous facilitation of pain and/or diminished diminished endogenous pain inhibition. Neuroanatomical pathways mediating these effects are examined.

The objective was to investigate the 3-year course of secondary chronic headaches (⩾15days per month for at least 3months) in the general population. An age and gender stratified random sample of 30,000 persons aged 30-44years from the general population received a mailed questionnaire. All with self-reported chronic headache, 517 in total, were interviewed by neurological residents. The questionnaire response rate was 71%. The rate of participation in the initial and follow-up interview was 74% (633/852) and 87% (83/95) respectively. The International Classification of Headache Disorders was used, and then in the next step the Cervicogenic Headache International Study Group and American Academy of Otolaryngology criteria were used in relation to cervicogenic headache (CEH) and headache attributed to chronic rhinosinusitis (HACRS). Of those followed-up, 40 had headache attributed to head and/or neck trauma (chronic posttraumatic headache), 0 had CEH and 0 had HACRS according to the ICHD-II criteria, while 18 had CEH according to the Cervicogenic Headache International Study Group's criteria, and 37 had HACRS according to the criteria of the American Academy of Otolaryngology. The headache index (frequency×intensity×duration) was significantly reduced from baseline to follow-up in chronic posttraumatic headache and HACRS, but not in CEH. We conclude that secondary chronic headaches seem to have various course dependent of subtype. Recognizing the different types of secondary chronic headaches is of importance because it might have management implications., (Copyright © 2010 European Federation of International Association for the Study of Pain Chapters. Published by Elsevier Ltd. All rights reserved.)

Medication-overuse headache (MOH) is a syndrome that can develop in migraineurs after overuse of antimigraine drugs, including opiates and triptans especially. MOH manifests as increased frequency and intensity of migraine attacks and enhanced sensitivity to stimuli that elicit migraine episodes. Although the mechanisms underlying MOH remain unknown, it is hypothesized that repeated use of antimigraine drugs could elicit increased headache attacks as a consequence of neuronal plasticity that may increase responsiveness to migraine triggers. Preclinical studies show that exposure to either opiates or triptans can induce pronociceptive neuroadaptive changes in the orofacial division of the trigeminal ganglia that persist even after discontinuation of the drug treatment. Additionally, medications can elicit increased descending facilitatory influences that may amplify evoked inputs from trigeminal afferents leading to behavioral hypersensitivity reminiscent of cutaneous allodynia observed clinically. Importantly, enhanced descending facilitation may manifest as an inhibition of diffuse noxious inhibitory control. Persistent, pronociceptive adaptations in nociceptors as well as within descending modulatory pathways thus may jointly contribute to the development of MOH.

Background: Medication-overuse headache (MOH) is a frequent, disabling disorder. Despite a controversial pathophysiology convincing evidence attributes a pivotal role to central sensitization. Most patients with MOH initially have episodic migraine without aura (MOA) characterized interictally by an absent amplitude decrease in cortical evoked potentials to repetitive stimuli (habituation deficit), despite a normal initial amplitude (lack of sensitization). Whether central sensitization alters this electrophysiological profile is unknown. We therefore sought differences in somatosensory evoked potential (SEP) sensitization and habituation in patients with MOH and episodic MOA., Methods: We recorded median-nerve SEPs (3 blocks of 100 sweeps) in 29 patients with MOH, 64 with MOA and 42 controls. Episodic migraineurs were studied during and between attacks. We measured N20-P25 amplitudes from 3 blocks of 100 sweeps, and assessed sensitization from block 1 amplitude, and habituation from amplitude changes between the 3 sequential blocks., Results: In episodic migraineurs, interictal SEP amplitudes were normal in block 1, but thereafter failed to habituate. Ictal SEP amplitudes increased in block 1, then habituated normally. Patients with MOH had larger-amplitude block 1 SEPs than controls, and also lacked SEP habituation. SEP amplitudes were smaller in triptan overusers than in patients overusing nonsteroidal anti-inflammatory drugs (NSAIDs) or both medications combined, lowest in patients with the longest migraine history, and highest in those with the longest-lasting headache chronification., Conclusions: In patients with MOH, especially those overusing NSAIDs, the somatosensory cortex becomes increasingly sensitized. Sensory sensitization might add to the behavioral sensitization that favors compulsive drug intake, and may reflect drug-induced changes in central serotoninergic transmission.

Medication-overuse headache (MOH) can be viewed as an interaction between the worsening of the primary headache course and individual predispositions for dependence. We present here a review of the clinical and biological data raising the role of dependence-related behavior in MOH. Indeed, several clinical studies show that acute headache medications containing psychoactive components (barbiturates, opiates) are associated with an increased risk of MOH. Diagnostic and Statistical Manual of Mental Disorders, 4th edition substance dependence criteria were identified in a sub-group of MOH patients. Comorbidity between MOH and substance-related disorders has also been showed. Recent neuroimaging, biological, and pharmacogenetic studies suggest the existence of an overlap between the pathophysiological mechanisms of MOH and those of substance-related disorders. These data support the proposition of separating 2 sets of MOH patients: the first one in which the illness is mainly due to the worsening of the headache course, and the second one in which behavioral issues are a major determinant of the illness. Detection of a psychological dependence component in a sub-group of MOH patients should have direct relevance to disease management., (© 2010 American Headache Society.)

Chronification of migraine headaches is one of the most urgent issues. Chronic migraine (CM) and medication overuse headache (MOH) are defined in international classification of headache disorders II (ICHD-II). Appendix criteria of CM and MOH were submitted and will take over the original criteria. I described a case of CM and a case of MOH. Here I pointed out some practical issues in diagnosis of CM or MOH. 1) It is not easy to define the association of headache worsening and the beginning of medication overuse in many cases. 2) Some patients cannot discontinue the overused drugs; therefore, the diagnosis of CM nor MOH cannot be completed. 3) Some patients are not released from their headache even after the discontinuation of drug. In these cases, there are two possibilities. As a result of CM, the patient had simply overused the ineffective medications. From another point of view, MOH caused irreversible brain changes and MOH do not disappear after the detoxification. 4) In a practical management, we often prescribe preventive medications simultaneously at the beginning of detoxification. In these cases, it is unclear which one of the detoxification or the preventive medication contributes the improvement of headache. The chronification of migraine is regarded as chronification of acute mechanism of migraine, i.e., inflammation of the trigeminovascular system and sensitization of the brain. Apart from medication overuse, there have been reported some new risk factors for migraine chronification, including frequent headache, female sex, obesity, low income, low education, stress by life events, depression, snoring, sleep disorders, and past history of neck or head injury. Chronification of migraine severely disturbs the quality of patient's life. More attention should be paid and the further and extensive studies are urgently necessary.

The present study was conducted to determine the effect of acute (1 h) and chronic (daily dose for 30 days) paracetamol administration on the development of cortical spreading depression (CSD), CSD-evoked cortical hyperaemia and CSD-induced Fos expression in cerebral cortex and trigeminal nucleus caudalis (TNC). Paracetamol (200 mg/kg body weight, intraperitonealy) was administered to Wistar rats. CSD was elicited by topical application of solid KCl. Electrocorticogram and cortical blood flow were recorded. Results revealed that acute paracetamol administration substantially decreased the number of Fos-immunoreactive cells in the parietal cortex and TNC without causing change in CSD frequency. On the other hand, chronic paracetamol administration led to an increase in CSD frequency as well as CSD-evoked Fos expression in parietal cortex and TNC, indicating an increase in cortical excitability and facilitation of trigeminal nociception. Alteration of cortical excitability which leads to an increased susceptibility of CSD development can be a possible mechanism underlying medication-overuse headache.

Chronic daily headache (CDH) is a descriptive term that encompasses multiple headache diagnoses and affects approximately 4% of the general adult population. Chronic daily headache results in significant pain and suffering with substantial impact on quality of life, and enormous economic costs to society. Although most patients with primary CDH suffer from chronic migraine or chronic tension-type headache, other primary and secondary headache disorders can also manifest as a CDH syndrome. For CDH management to succeed, secondary headaches need to be ruled out with proper investigations when judged necessary. If the diagnosis of primary CDH is established, diagnosis of the specific CDH subtype is imperative to institute appropriate treatment. The diagnosis and management of distinct CDH entities, chronic migraine, chronic tension-type headache, new daily persistent headache, and hemicrania continua, are the primary forms of CDH and the emphasis of this review. Although, strictly speaking, medication overuse headache is a secondary form of CDH, it is also highlighted in this review given its frequent association with primary CDH., (Thieme Medical Publishers.)

Medication-overuse headache (MOH) is a chronic headache disorder defined by the International Headache Society as a headache induced by the overuse of analgesics, triptans, or other acute headache compounds. The population-based prevalence of MOH is 0.7% to 1.7%. Most patients with MOH have migraine as their primary headache and overuse triptans or simple analgesics. The pathophysiology of MOH is still unknown. As well as psychological mechanisms such as operant conditioning, changes in endocrinological homoeostasis and neurophysiological changes have been observed in patients with MOH. Recently, a genetic susceptibility has been postulated. In most cases, treatment of MOH consists of abrupt withdrawal therapy and then initiation of an appropriate preventive drug therapy. There is no clear evidence on which method of withdrawal therapy is the most efficacious. Withdrawal symptoms can be treated with steroids; however, not all data support this concept. As MOH can severely affect the quality of life of patients, it needs to be recognised early to enable appropriate treatment to be initiated., (2010 Elsevier Ltd. All rights reserved.)

Objective: Identification of the neural mechanisms underlying medication overuse headache resulting from triptans., Methods: Triptans were administered systemically to rats by repeated intermittent injections or by continuous infusion over 6 days. Periorbital and hind paw sensory thresholds were measured to detect cutaneous allodynia. Immunofluorescent histochemistry was employed to detect changes in peptidic neurotransmitter expression in identified dural afferents. Enzyme-linked immunoabsorbent assay was used to measure calcitonin gene-related peptide (CGRP) levels in blood., Results: Sustained or repeated administration of triptans to rats elicited time-dependent and reversible cutaneous tactile allodynia that was maintained throughout and transiently after drug delivery. Triptan administration increased labeling for CGRP in identified trigeminal dural afferents that persisted long after discontinuation of triptan exposure. Two weeks after triptan exposure, when sensory thresholds returned to baseline levels, rats showed enhanced cutaneous allodynia and increased CGRP in the blood following challenge with a nitric oxide donor. Triptan treatment thus induces a state of latent sensitization characterized by persistent pronociceptive neural adaptations in dural afferents and enhanced responses to an established trigger of migraine headache in humans., Interpretation: Triptans represent the treatment of choice for moderate and severe migraine headaches. However, triptan overuse can lead to an increased frequency of migraine headache. Overuse of these medications could induce neural adaptations that result in a state of latent sensitization, which might increase sensitivity to migraine triggers. The latent sensitization could provide a mechanistic basis for the transformation of migraine to medication overuse headache.

Medication overuse could interfere with the activity of critical brain regions involved in the supraspinal control of pain signals at the trigeminal and spinal level, leading to a sensitisation phenomenon responsible for chronic pain. We hypothesised that medication-overuse headache (MOH) patients might display abnormal processing of pain stimuli at the spinal level and defective functioning of the diffuse noxious inhibitory controls. We tested 31 MOH patients before (bWT) and after (aWT) standard inpatient withdrawal treatment, 28 episodic migraine (EM) patients and 23 healthy control subjects. We measured the threshold, the area and the temporal summation threshold (TST) of the nociceptive withdrawal reflex before, during and after activation of the diffuse noxious inhibitory controls by means of the cold pressor test. A significantly lower TST was found in both the MOH (bWT and aWT) and the EM patients compared with the controls, and in the MOH patients bWT compared with both the MOH patients aWT and the EM patients. In the MOH bWT patients the cold pressor test induced a TST increase significantly lower than that found in the MOH aWT, EM and control groups. Abnormal spinal cord pain processing and a decrease of the antinociceptive activity of the supraspinal structures in MOH patients can be hypothesised. These abnormalities could, in part, be related to the medication overuse, given that the withdrawal treatment was related to an improvement in the neurophysiological findings.

Objectives: To determine the involvement of 5-HT(2A) (5-HT(2A)) receptor in the process of trigeminal plasticity induced by chronic analgesic exposure and in the process of inflammatory-induced thermal hyperalgesia., Background: Derangement in 5-HT(2A) serotonin receptor has been reported to implicate in pathogenesis of medication-overuse headache. No clear explanation concerning the precise roles of these receptors in the process., Methods: Wistar rats were daily administered with paracetamol (200 mg/kg) for 30 days. On the next day, ketanserin, a 5-HT(2A) antagonist, or saline was given prior to cortical spreading depression (CSD) induction. Electrocorticogram, cortical blood flow, Fos and 5-HT(2A)-immunoreactivity in cortex and trigeminal pathway were studied. In the other experiment, complete Freund's adjuvant was injected into the rat hind paw to induce tissue inflammation. Three days later, ketanserin was given and noxious heat was applied to both inflamed and noninflamed paws. The response between 2 sides was compared by measuring paw withdrawal latency., Results: Chronic paracetamol exposure led to an increase in CSD frequency and CSD-evoked Fos expression in cerebral cortex indicating the increase in neuronal excitability. Prolonged medication exposure also facilitated trigeminal nociception as evident by an increase in CSD-evoked Fos expression in trigeminal nucleus caudalis. The expression of 5-HT(2A) receptor in cerebral cortex and trigeminal ganglia was enhanced by chronic paracetamol administration. Pretreatment with ketanserin significantly attenuated these effects. The second experiment showed that ketanserin was able to lengthen the paw withdrawal latency in the inflamed side but did not alter nociceptive response in the noninflamed side., Conclusion: These findings suggest that up-regulation of pro-nociceptive 5-HT(2A) receptor is an important step in the process of cortical hyper-excitation and nociceptive facilitation induced by chronic analgesic exposure.

Characteristics of brain evoked activity were studied in patients with most frequent variants of secondary headaches: chronic posttraumatic headaches, cervicogenic headaches and vascular headaches in patients with arterial hypertension and chronic brain ischemia. The multimodal registration of evoked potentials (EP) (short-latency brainstem auditory, visual EPs to flash stimulation and cognitive EPs - P300) revealed signs of brainstem dysfunction, decrease of visual analyzer and diminished cognitive functions in most patients with secondary headaches. Based on results obtained, we can recommend a complex therapy of chronic secondary headaches with neuroprotectors and nootropics.

The management of medication overuse headache (MOH) is based essentially on the withdrawal of the overused drug(s). Drug withdrawal is performed according to widely differing protocols, both within and across countries; therefore, therapeutic recommendations for the acute phase of detoxification vary considerably among studies. Basically, the aims of MOH management are: (a) to withdraw the overused drug(s); (b) to alleviate withdrawal symptoms by means of a bridge therapy, which includes pharmacological and non-pharmacological support, designed to help the patient to tolerate the withdrawal process; (c) to prevent relapse. Today, there is extensive debate over the best strategies for achieving these goals and the different aspects of this debate are discussed in this review. The authors searched for the best available evidence relating to the following questions: should medication withdrawal be abrupt or gradual? Should patients receive replacement therapy? What are the most effective therapeutic programmes for controlling withdrawal symptoms? Should replacement therapy be administered routinely or as rescue therapy? Should preventive treatment be started before, during or after withdrawal? What are the most effective preventive treatments? Should patients be managed through inpatient or outpatient withdrawal programmes? What is the best approach to adopt in preventing relapses? Treatment of MOH is a difficult challenge, but may be very rewarding. Although there is still a lack of high-quality studies providing evidence-based answers to the many specific questions it raises, neurologists need to know that the combination of education with a rational use of selected therapeutic strategies may be beneficial to people with chronic headache and help to relieve their suffering.

Medication overuse headache (MOH) is a challenging, debilitating disorder that develops from the frequent use of medications taken for the treatment of migraine headache pain. MOH affects an estimated 3-5% of the general population. The mechanisms underlying the development of MOH remain unknown. Opiates are one of the major classes of medications used for the treatment of migraine at least in some countries, including the USA. Although the effects of repeated opiate use for headache are unknown, it is possible that opiate use may contribute to increased frequency and occurrence of such headaches. Recent preclinical studies exploring the neuroadaptive changes following sustained exposure to morphine may give some insights into possible causes of MOH. Peripherally, these changes include increased expression of calcitonin gene-related peptide (CGRP) in trigeminal primary afferent neurons. Centrally, they include increased excitatory neurotransmission at the level of the dorsal horn and nucleus caudalis. Critically, these neuroadaptive changes persist for long periods of time and the evoked release of CGRP is enhanced following morphine pretreatment. Stimuli known to elicit migraine, such as nitric oxide donors or stress, produce hyperalgesia in morphine- but not in saline-pretreated rats even long after the discontinuation of the opiate. CGRP plays a prominent role in initiating vasodilation of the intracranial blood vessels and subsequent headache. Furthermore, studies have demonstrated increased excitability of the nociceptive pathway in migraine sufferers, and CGRP receptor antagonists have been shown to be efficacious in migraine pain. Thus, such persistent neuroadaptive changes may be relevant to the processes that promote MOH.

Tension-type headache (TTH) is the most prevalent primary headache disorder. An important factor in the long-term prognosis of TTH is the overuse of acute medications used to treat headache. There are many reasons why patients with TTH overuse acute medications, including biobehavioral influences, dependency, and a lack of patient education. Chronic daily headache occurs in 4.1% of the general population, and chronic tension-type headache and medication overuse headache (MOH) occur in approximately 2.2% and 1.5%, respectively. A proper diagnosis is essential for the treatment of these patients. Treatment should include pathological considerations concerning TTH and MOH, which include peripheral and central mechanisms. Because TTH with MOH carries the worst prognosis, more clinical studies focusing on the complex interaction and treatments of TTH and MOH are needed.

Objective: To explore the effect of symptomatic medication overuse (SMO) and headache type on occipital nerve block (ONB) efficacy., Methods: We conducted a chart review of all of the ONBs performed in our clinic over a 2-year period., Results: Of 108 ONBs with follow-up data, ONB failed in 22% of injections overall. Of the other 78%, the mean decrease in head pain was 83%, and the benefit lasted a mean of 6.6 weeks. Failure rate without SMO was 16% overall, and with SMO was 44% overall (P < .000). In those who did respond, overall magnitude and duration of response did not differ between those with and those without SMO. Without SMO, ONB failure rate was 0% for postconcussive syndrome, 14% for occipital neuralgia, 11% for non-intractable migraine, and 39% for intractable migraine. With SMO, failure rate increased by 24% (P = .14) in occipital neuralgia, by 36% (P = .08) for all migraine, and by 52% (P = .04) for non-intractable migraine., Conclusions: SMO tripled the risk of ONB failure, possibly because medication overuse headache does not respond to ONB. SMO increased ONB failure rate more in migraineurs than in those with occipital neuralgia, possibly because migraineurs are particularly susceptible to medication overuse headache. This effect was much more pronounced in non-intractable migraineurs than in intractable migraineurs.

We report the case of a 44-year-old woman with chronic facial pain. She was treated with several analgesics, prophylactic medications and infiltrations, but all treatment modalities were ineffective. Finally, the diagnosis of medication-overuse headache complicating migraine without aura was made and an appropriate treatment was initiated. Migraine is a very common primary headache and rarely presents as isolated facial pain. Stimulation of the dura with activation of the trigeminovascular system can result in pain in any of the three divisions of the trigeminal nerve. This is the anatomic basis of migraine pain presenting as referred pain to the second division of the trigeminal nerve. The atypical presentation of migraine pain can easily lead to inappropriate treatment regimens.

Hemicrania continua (HC) is an indomethacin responsive primary headache disorder. Secondary or symptomatic HC is associated with another neurological or non-neurological disease. We report three patients with secondary HC. We also review the literature to identify the clinical predictors of an underlying disease entity. Intracranial structural lesion, head and neck vessel pathology, and carcinoma lung should be suspected in every patient. The factors that may suggest a secondary pathology are: elderly age, male sex, smoking habit, constitutional symptoms, symptoms related to respiratory system, frequent and short-lived exacerbation, nocturnal exacerbation, HC evolving from remitting form, recent neck and/or head trauma, miosis, elevated ESR, and fading effect of indomethacin. We recommend MRI brain in all the patients presenting with HC or HC like headache. Angiography and CT chest are two other investigations that may be supplemented in patients with high risk for head/neck vessel pathology and carcinoma lung.

Withdrawal is the first step for treating patients with chronic migraine and medication overuse. Recent studies confirmed common elements in personality between these patients and subjects addicted; some neuroimaging researches showed that abnormalities revealed are related to a specific cerebral pattern and that they can return to the normal state after withdrawal. Aim of the study was to submit a group of patients suffering from chronic migraine and medication overuse (the diagnosis was made according to Silberstein-Lipton criteria) to a withdrawal, to evaluate by f-MRI the presence of specific cerebral patterns before treatment and their possible changes after withdrawal. f-MRI seems to be a useful technique to obtain information on particular neuronal changes of the pain network involved in this type of patients. The activated areas are congruent with some data of the literature and the data emerged are discussed according to preceding reports.

The purpose of this review was to provide a critical evaluation of medical literature on so-called "cardiac cephalgia" or "cardiac cephalalgia". The 2004 International Classification of Headache Disorders codes cardiac cephalgia to 10.6 in the group of secondary headaches attributed to disorder of homoeostasis. This headache is hardly recognizable and is associated to an ischaemic cardiovascular event, of which it may be the only manifestation in 27% of cases. It usually occurs after exertion. Sometimes routine examinations, cardiac enzymes, ECG and even exercise stress test prove negative. In such cases, only a coronary angiogram can provide sufficient evidence for diagnosis. Cardiac cephalgia manifests itself without a specific pattern of clinical features: indeed, in this headache subtype there is a high variability of clinical manifestations between different patients and also within the same patient. It "mimics" sometimes a form of migraine either accompanied or not by autonomic symptoms, sometimes a form of tension-type headache; on other occasions, it exhibits characteristics that can hardly be interpreted as typical of primary headache. Pain location is highly variable. When the headache occurs as the only manifestation of an acute coronary event, the clues for suspicion are a) older age at onset, b) no past medical history of headache, c) presence of risk factors for vascular disorders and d) onset of headache under stress. Knowledge of cardiac cephalgia is scarce, due to its rare clinical occurrence and to the scant importance given to headache as a symptom concomitantly with an ischaemic cardiac event.

It is a general belief that patients with medication overuse headache (MOH) need withdrawal of acute headache medication before they respond to prophylactic medication. In this 1-year open-labelled, multicentre study intention-to-treat analyses were performed on 56 patients with MOH. These were randomly assigned to receive prophylactic treatment from the start without detoxification, undergo a standard out-patient detoxification programme without prophylactic treatment from the start, or no specific treatment (5-month follow-up). The primary outcome measure, change in headache days per month, did not differ significantly between groups. However, the prophylaxis group had the greatest decrease in headache days compared with baseline, and also a significantly more pronounced reduction in total headache index (headache days/month x headache intensity x headache hours) at months 3 (P = 0.003) and 12 (P = 0.017) compared with the withdrawal group. At month 12, 53% of patients in the prophylaxis group had > or = 50% reduction in monthly headache days compared with 25% in the withdrawal group (P = 0.081). Early introduction of preventive treatment without a previous detoxification programme reduced total headache suffering more effectively compared with abrupt withdrawal. (ClinicalTrials.gov number, NCT00159588).

Clearly the patient's history is paramount in determining whether a headache belongs in the migraine, chronic tension-type or other category. The multiple conditions in the other category can sometimes make definitive diagnosis a daunting challenge. Laboratory testing looking for hematologic or metabolic abnormalities may be advised, and brain imaging may be required. If an acute hemorrhage is anticipated, an unenhanced CAT scan may be sufficient. Relative to other pathologic possibilities, a MRI generally provides more specific and useful information. This is especially true when seeking to rule out a tumor or vascular abnormality (in which case a MRA, as well as a MRI, may be helpful). Most lay people recognize that headaches may, at least potentially, have a serious cause. Indeed, many patients with severe migraine and chronic tension-type headaches are greatly relieved to learn that some ominous pathology is not present. Of course, clinicians also worry about the causes of headache and are fearful of missing some potentially serious underlying pathology. Utilization of the conceptual framework of migraine, chronic tension-type or other headache does not guarantee an accurate diagnosis. But this approach can help, especially when the clinician appreciates the importance of an accurate patient history. Such focus can guide the determination of whether to initiate empiric treatment or to embark on a definitive diagnostic evaluation. Headaches are common, sometimes disabling and potential harbingers of dreaded pathology. Thoughtful assessment of every patient with headache is warranted.