Brain Metabolism and Structure in Chronic Migraine.

PURPOSE OF REVIEW: The purpose of this paper is to review and synthesize current literature in which neurochemical and structural brain imaging were used to investigate chronic migraine (CM) pathophysiology and to further discuss the clinical implications. RECENT FINDINGS: Spectroscopic and structural MRI studies have shown the presence of both impaired metabolism and structural alterations in the brain of CM patients. Metabolic changes in key brain regions support the notion of altered energetics and homeostasis as part of CM pathophysiology. Furthermore, CM, like other chronic pain disorders, may undergo structural reorganization in pain-related brain regions following near persistent endogenous painful input. Finally, both imaging techniques may provide potential biomarkers of disease state and progression and may help guide novel therapeutic interventions or strategies. Spectroscopic and structural MRI have revealed novel aspects of CM pathophysiology. Findings from the former support the metabolic theory of migraine pathogenesis.

New treatments for headache.

Headache disorders are common worldwide and often disabling. Until recently, treatments were borrowed from other branches of neurology and medicine. Monoclonal antibodies targeting calcitonin gene-related peptide (CGRP) ligand and receptor, small molecule CGRP receptor antagonist gepants, serotonin1F agonists, new devices to deliver currently available drugs, and neuromodulation devices have recently been in the forefront of headache treatments that are rather specific for various headache disorders. These novel therapies are changing the field of headache medicine. Herein, we update the latest data available for these therapies.

Neurobiology of chronicization.

In the past few years, research on chronicization of headache has focussed primarily on migraine, even though there are other types of primary headache that over time can turn into chronic forms. Only a minority of migraine sufferers will develop a chronic condition, with attacks that are likely to vary in their clinical features. As a result, in chronic migraine the specific diagnostic criteria for this headache type do not always exhibit the typical features of migraine. Among the factors that play a major role in favouring chronicization are a high frequency of migraine attacks since the beginning, overuse of symptomatic medication and onset of depression or arterial hypertension. Several neurophysiology, biochemistry and functional neuroimaging studies suggest that chronic migraine may be associated with structural, functional and metabolic changes in the brain, especially involving the brainstem.

A neurometabolite study of chronic daily headache in patients with systemic lupus erythematosus using magnetic resonance spectroscopy: comparison with fibromyalgia patients and healthy controls.

BACKGROUND/AIMS: Neuropsychiatric systemic lupus erythematosus (SLE) includes a broad spectrum of neurologic and psychiatric manifestations. One of the most commonly observed neuropsychiatric symptoms is headache. However, the lack of specific clinical distinctions for headache in SLE has made it difficult to elucidate its pathophysiology. The aim of this study is to evaluate the neurometabolic changes using Proton Magnetic Resonance Spectroscopy (1H-MRS) in patients with SLE who suffer from chronic daily headache (CDH). METHODS: SLE and fibromyalgia patients with CDH and healthy controls were recruited (n = 9, n = 5, and n = 6, respectively). 1H-MRS metabolite ratios were evaluated in bilateral basal ganglia (BG) and bilateral peritrigonal white matter (PWM). RESULTS: 1H-MRS showed a significantly decreased N-acetylaspartate (NAA)/creatine (Cr) ratio in right BG in SLE patients with CDH compared to fibromyalgia patients with CDH and normal controls (p = 0.029 and p = 0.020, respectively). Left PWM NAA/Cr and choline/Cr ratios in SLE patients with CDH were lower than those in fibromyalgia patients with CDH (p = 0.019 and p = 0.029, respectively). CONCLUSIONS: This study suggests the possibility that CDH in patients with SLE might be associated with neuronal dysfunction and neurometabolic changes.

Oxytocin receptor: Expression in the trigeminal nociceptive system and potential role in the treatment of headache disorders.

AIMS: Our studies investigated the location of oxytocin receptors in the peripheral trigeminal sensory system and determined their role in trigeminal pain. METHODS: Oxytocin receptor expression and co-localization with calcitonin gene-related peptide was investigated in rat trigeminal ganglion using immunohistochemistry. Enzyme-linked immunosorbent assay was used to determine the effects of facial electrocutaneous stimulation and adjuvant-induced inflammation of the temporomandibular joint on oxytocin receptor expression in the trigeminal ganglion. Finally, the effects of oxytocin on capsaicin-induced calcitonin gene-related peptide release from dural nociceptors were investigated using isolated rat dura mater. RESULTS: Oxytocin receptor immunoreactivity was present in rat trigeminal neurons. The vast majority of oxytocin receptor immunoreactive neurons co-expressed calcitonin gene-related peptide. Both electrocutaneous stimulation and adjuvant-induced inflammation led to a rapid upregulation of oxytocin receptor protein expression in trigeminal ganglion neurons. Oxytocin significantly and dose-dependently decreased capsaicin-induced calcitonin gene-related peptide release from dural nociceptors. CONCLUSION: Oxytocin receptor expression in calcitonin gene-related peptide containing trigeminal ganglion neurons, and the blockade of calcitonin gene-related peptide release from trigeminal dural afferents suggests that activation of these receptors may provide therapeutic benefit in patients with migraine and other primary headache disorders.

14th International Headache Congress: clinical highlights.

The 14th International Headache Congress was held in Philadelphia in September 2009. During the Congress, many important basic, translational, and patient-oriented research studies were presented. In this and an accompanying manuscript, the work that has been deemed to be among the most innovative and significant is summarized. This manuscript discusses the best clinical research, while the accompanying manuscript summarizes the top basic science research. Here, we provide background and summarize Congress presentations on novel agents for migraine treatment, botulinum toxin therapy for chronic migraine, new methods for administration of headache medications, and nerve stimulation for the treatment of medically refractory headaches.

The effect of pregnancy and parity on headache prevalence: the Head-HUNT study.

BACKGROUND: In previous studies, pregnancy has been associated with less headache, but the influence of parity on this association is largely unknown. OBJECTIVES: To examine the prevalence of headache and migraine among pregnant women, and explore the relation of headache to parity in a large, population-based study. METHODS: In the Nord-Trøndelag Health Study in Norway 1995-1997 (HUNT 2), a total of 27,700 (60%) out of 46,506 invited women responded to headache questions (Head-HUNT). In total, 9281 women were 40 years or younger and responded to questions on pregnancy and birth, and 550 of these reported to be pregnant when filling in the questionnaire. A total of 20,287 women who were 70 years or younger and reported not to be pregnant responded to questions on headache and reported number of child births. RESULTS: Adjusting for age and educational level, the headache prevalence was lower among pregnant than among nonpregnant women. The association between headache and pregnancy was significant for nulliparous (one who has never given birth) (OR = 0.5, 95% CI = 0.4-0.7), but not for primiparous (1 child only) and multiparous (several children) women (OR = 0.8, 95% CI = 0.7-1.0). This was evident for both migraine and nonmigrainous headache. Among nonpregnant women, there was an increased headache prevalence among primi- and multiparous women compared with nulliparous (OR = 1.3, 95% CI = 1.2-1.4). CONCLUSION: Headache, both migraine and nonmigrainous, was less prevalent in nulliparous pregnant women compared with all nonpregnant women, and to nulliparous nonpregnant women. Headache was less prevalent in the third trimester of pregnancy, but not in the first and second trimesters, compared with nonpregnant women. Also in nonpregnant women, headache was less prevalent in nulliparous than in primi- and multiparous women.

Oligomerization state-dependent elevations of adiponectin in chronic daily headache.

OBJECTIVE: To evaluate serum adiponectin levels in female episodic migraineurs (EMs) and chronic daily headache (CDH) sufferers. BACKGROUND: Obesity is a risk factor for headache "chronification." Adiponectin (ADP) is an adipocytokine secreted primarily by adipose tissue. ADP and its oligomers (high-molecular-weight [HMW], middle-molecular-weight [MMW], and low-molecular-weight [LMW] ADP) have been shown to modulate several inflammatory pathways that have also been shown to be associated with migraine pathophysiology. METHODS: Age- and body mass index (BMI)-matched women participants were enrolled. Anthropometric measures (including waist-to-hip ratio [WHR] and BMI) were measured in all participants. Serum total ADP (T-ADP) levels and its oligomers were measured in EMs during headache-free periods and CDH sufferers at baseline level of pain, as compared with healthy control subjects using ELISA. RESULTS: Although total body obesity as estimated by BMI showed no significant association between participants, visceral obesity as estimated by WHR was significantly associated with CDH as compared with EMs and controls. WHR was also inversely related to both T-ADP (p = 0.008) and HMW-ADP (p = 0.002). After adjusting for WHR, serum T-ADP levels were higher in CDH sufferers (10.1 +/- 4.0) than in both EMs (8.6 +/- 3.5) and controls (7.5 +/- 2.4) (p = 0.024). In addition, HMW-ADP was higher in CDH (6.1 +/- 2.8) as compared with EMs (4.2 +/- 1.7) and controls (3.9 +/- 1.5) (p = 0.003). MMW-ADP was also higher in CDH (2.0 +/- 1.2) as compared with EMs (1.5 +/- 0.7) and controls (1.1 +/- 0.4) (p = 0.009). CONCLUSION: Serum adiponectin levels are increased in women chronic daily headache (CDH) sufferers. In addition, visceral obesity, as measured by waist-to-hip ratio, is a risk factor for CDH in women.

A review of the literature on the cognitive effects of alcohol hangover.

AIMS: Alcohol misuse is a prime social and health problem in the UK. This paper presents a critical review of literature on the performance effects in the morning after binge drinking - during the alcohol hangover. Several pathophysiological changes that both follow and outlast acute intoxication may give rise to alcohol hangover effects. We have identified 27 English language peer-reviewed studies that investigate aspects of psychological performance during alcohol hangover following controlled alcohol ingestion. However, the majority of studies had basic methodological shortcomings. Of eight laboratory studies rigorous enough to warrant serious attention, only two showed effects. We interpret these largely negative findings as evidence of an insensitivity that is intrinsic to laboratory-based studies of performance under the influence of alcohol. Several studies have investigated the cognitive consequences of hangover subsequent to naturalistic consumption, where participants have chosen what and where to drink. Although these studies have tended to show effects, participants were always informed at the outset that hangover effects were to be assessed, and participants knew which was the hangover condition. Under these circumstances expectancy effects have possibly contaminated the results significantly. Therefore, naturalistic alcohol consumption studies (and laboratory studies that did not employ a placebo) can be considered as being suggestive of hangover effects, but should not be interpreted as providing definitive evidence of such effects. In conclusion, although there is empirical evidence showing impaired performance as a result of the alcohol hangover, future studies should confirm these findings and overcome the shortcomings of previous research.

Recent advances in the pharmacogenomics of pain and headache.

Liability to spontaneous and experimental pain is genetically determined and there is considerable variability in the antinociceptive effects of drugs commonly used in treating pain conditions and migraine attacks. The causes for variability involve still unknown genetic aspects. Recently, a third gene, SCN1A, was discovered as a cause of familial hemiplegic migraine (FHM). Recent advances in the genetics of pain and pain disorders include the discovery of the role of the sodium ion channel SCN9A in neuropathic pain as well as in inability to experience pain, and of GTP cyclohydrolase (GCH1) in setting the sensitivity to pain in normal individuals and modulating liability to chronic pain. Catechol-O-methyltransferase (COMT) and the cytochrome P450 variant allele CYP3A5 modulate the genetic response to opioid medications in humans. Variability in drug pharmacokinetics and adverse drug reactions of pain medications are also very much related to genetic variation, especially in CYP genes. Pharmacogenomic studies of headache and pain are still in their infancy, but these recent advances in the genetics of migraine and pain arguably hold the promise of individualised treatments and prevention of adverse drug reactions.

Pharmacokinetics and interactions of headache medications, part I: introduction, pharmacokinetics, metabolism and acute treatments.

Recent progress in the treatment of primary headaches has made available specific, effective and safe medications for these disorders, which are widely spread among the general population. One of the negative consequences of this undoubtedly positive progress is the risk of drug-drug interactions. This review is the first in a two-part series on pharmacokinetic drug-drug interactions of headache medications. Part I addresses acute treatments. Part II focuses on prophylactic treatments. The overall aim of this series is to increase the awareness of physicians, either primary care providers or specialists, regarding this topic. Pharmacokinetic drug-drug interactions of major severity involving acute medications are a minority among those reported in literature. The main drug combinations to avoid are: i) NSAIDs plus drugs with a narrow therapeutic range (i.e., digoxin, methotrexate, etc.); ii) sumatriptan, rizatriptan or zolmitriptan plus monoamine oxidase inhibitors; iii) substrates and inhibitors of CYP2D6 (i.e., chlorpromazine, metoclopramide, etc.) and -3A4 (i.e., ergot derivatives, eletriptan, etc.), as well as other substrates or inhibitors of the same CYP isoenzymes. The risk of having clinically significant pharmacokinetic drug-drug interactions seems to be limited in patients with low frequency headaches, but could be higher in chronic headache sufferers with medication overuse.

Pharmacokinetics and interactions of headache medications, part II: prophylactic treatments.

The present part II review highlights pharmacokinetic drug-drug interactions (excluding those of minor severity) of medications used in prophylactic treatment of the main primary headaches (migraine, tension-type and cluster headache). The principles of pharmacokinetics and metabolism, and the interactions of medications for acute treatment are examined in part I. The overall goal of this series of two reviews is to increase the awareness of physicians, primary care providers and specialists regarding pharmacokinetic drug-drug interactions (DDIs) of headache medications. The aim of prophylactic treatment is to reduce the frequency of headache attacks using beta-blockers, calcium-channel blockers, antidepressants, antiepileptics, lithium, serotonin antagonists, corticosteroids and muscle relaxants, which must be taken daily for long periods. During treatment the patient often continues to take symptomatic drugs for the attack, and may need other medications for associated or new-onset illnesses. DDIs can, therefore, occur. As a whole, DDIs of clinical relevance concerning prophylactic drugs are a limited number. Their effects can be prevented by starting the treatment with low dosages, which should be gradually increased depending on response and side effects, while frequently monitoring the patient and plasma levels of other possible coadministered drugs with a narrow therapeutic range. Most headache medications are substrates of CYP2D6 (e.g., beta-blockers, antidepressants) or CYP3A4 (e.g., calcium-channel blockers, selective serotonin re-uptake inhibitors, corticosteroids). The inducers and, especially, the inhibitors of these isoenzymes should be carefully coadministered.

[Alteration of the antinociceptive systems in chronic daily headaches]. / Alteracion de los sistemas antinociceptivos en las cefaleas cronicas diarias.

INTRODUCTION: Chronic daily headache (CDH) is a chronic painful clinical condition that is frequently found in neurological practice. Diagnosis is clinical and the therapeutic approach is complex. Its mechanism of production is still not altogether clear, but a genetic component is acknowledged as a predisposing factor. Numerous areas are involved in the generation of primary headaches, including the periaqueductal grey matter (PAGM), which plays a role as a neuromodulator both in headaches and in other chronic painful conditions. AIMS: In order to evaluate possible biochemical changes in patients with CDH, magnetic resonance imaging was used to study the spectra produced in the PAGM. SUBJECTS AND METHODS: The spectra in the PAGM were studied in 17 patients with CDH. These were compared with the average spectra in 17 healthy subjects by means of differential spectroscopy. RESULTS: Subjects with CDH show a reduction of over 70% in the level of the metabolite N-acetyl-aspartyl-glutamate (NAAG) in the PAGM. NAAG is a peptide involved in antinociceptive activity. CONCLUSIONS: The reduction of NAAG in the PAGM suggests altered neuromodulation of the antinociceptive systems in subjects with CDH. Whether CDH is the cause or the consequence has still to be determined.

Potential therapeutic use of melatonin in migraine and other headache disorders.

There is increasing evidence that headache disorders are connected with melatonin secretion and pineal function. Some headaches have a clearcut seasonal and circadian pattern, such as cluster and hypnic headaches. Melatonin levels have been found to be decreased in both migraine and cluster headaches. Melatonin mechanisms are related to headache pathophysiology in many ways, including its anti-inflammatory effect, toxic free radical scavenging, reduction of pro-inflammatory cytokine upregulation, nitric oxide synthase activity and dopamine release inhibition, membrane stabilisation, GABA and opioid analgesia potentitation, glutamate neurotoxicity protection, neurovascular regulation, 5-HT modulation and the similarity in chemical structure to indometacin. The treatment of headache disorders with melatonin and other chronobiotic agents, such as melatonin agonists (ramelteon and agomelatin), is promising and there is a great potential for their use in headache treatment.

Pediatric SUNCT Syndrome.

This report describes a 5-year-old male with sudden unilateral headache attacks (2-50 seconds) accompanied by conjunctival injection, lacrimation, and nasal congestion. The episodes occurred without a precipitating factor, never during sleep. Brain imaging was normal. The attacks resolved spontaneously within 5 months. This headache syndrome (short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing) was previously described in two other children aged 10 and 11.

Neurobiology in primary headaches.

Primary headaches such as migraine and cluster headache are neurovascular disorders. Migraine is a painful, incapacitating disease that affects a large portion of the adult population with a substantial economic burden on society. The disorder is characterised by recurrent unilateral headaches, usually accompanied by nausea, vomiting, photophobia and/or phonophobia. A number of hypothesis have emerged to explain the specific causes of migraine. Current theories suggest that the initiation of a migraine attack involves a primary central nervous system (CNS) event. It has been suggested that a mutation in a calcium gene channel renders the individual more sensitive to environmental factors, resulting in a wave of cortical spreading depression when the attack is initiated. Genetically, migraine is a complex familial disorder in which the severity and the susceptibility of individuals are most likely governed by several genes that vary between families. Genom wide scans have been performed in migraine with susceptibility regions on several chromosomes some are associated with altered calcium channel function. With positron emission tomography (PET), a migraine active region has been pointed out in the brainstem. In cluster headache, PET studies have implicated a specific active locus in the posterior hypothalamus. Both migraine and cluster headache involve activation of the trigeminovascular system. In support, there is a clear association between the head pain and the release of the neuropeptide calcitonin gene-related peptide (CGRP) from the trigeminovascular system. In cluster headache there is, in addition, release of the parasympathetic neuropeptide vasoactive intestinal peptide (VIP) that is coupled to facial vasomotor symptoms. Triptan administration, activating the 5-HT(1B/1D) receptors, causes the headache to subside and the levels of neuropeptides to normalise, in part through presynaptic inhibition of the cranial sensory nerves. These data suggest a central role for sensory and parasympathetic mechanisms in the pathophysiology of primary headaches. The positive clinical trial with a CGRP receptor antagonist offers a new promising way of treatment.

Functional neuroimaging of headaches.

Functional neuroimaging, mainly PET and functional MRI, is the main tool that allows the capturing of neurovascular events during a headache attack. In migraine, functional imaging has clarified the underlying pathophysiology of the visual aura, whereas in migraine without aura, brainstem findings suggest a dysfunctional pain system. In cluster headache, the activation and morphological changes seen in a region posterior and inferior to the hypothalamus has provided a useful therapeutic target using deep-brain stimulation. We will discuss the main neuroimaging findings pertaining to the pathophysiology of these two common headache disorders, migraine and cluster headache.