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The information presented here on headache was part of the scientific program of the American Academy of Neurology (AAN) 58th Annual Meeting, which was held from April 1 to April 8, 2006 in San Diego, California.
Obesity has been proposed as a risk factor for the development of chronic daily headaches. Scientists have predicted that body mass index (BMI) may influence the prevalence, attack frequency, and clinical features of migraine. Researchers assessed the influence of BMI on the prevalence of migraine and its clinical features in a population-based telephone-interview study. They gathered information on headache and medical features, height, and weight, and divided participants into 5 categories that were based on BMI: underweight (< 18.5), normal-weight (18.5-24.9), overweight (25-29.9), obese (30-24.9), and morbidly obese (≥ 35). They assessed migraine prevalence and modeled headache features as a function of BMI, adjusting by covariates.
Among 30,215 individuals (65% women; mean age, 38.4), BMI classification was not associated with the prevalence of migraine, but it was associated with the frequency of headache attacks. In the normal-weight group, 4.4% of subjects had 10-15 headache-days per month. In comparison, 5.8% of subjects in the overweight group (odds ratio [OR], 1.3), 13.6% of those in the obese group (OR, 2.9), and 20.7% of those in the morbidly obese (OR, 5.7) group had 10-15 headache-days per month. The proportion of subjects with severe headache pain increased with higher BMI; it was doubled in the morbidly obese group relative to the normal-weight group (OR, 1.9). Similar significant associations were demonstrated with BMI category for disability, photophobia, and phonophobia. In the logistic regression model, after adjusting for covariates (sex, age, use of headache medications, sleep problems, education status, and depression), migraine attack frequency significantly changed as a function of BMI (P < .001). A BMI higher than 30 was also significantly associated with high pain severity (P < .001), high disability (P < .01), and with the proportion of attacks accompanied by photophobia and phonophobia (P < .01). The study authors concluded that although obesity is not a risk factor for having migraine, it is a risk factor for increased attack frequency and severity in those who have migraine.
Studies have shown that patients often develop cutaneous allodynia, a painful response from nonpainful stimuli, during migraine attacks. They proposed that the underlying mechanism involved is sensitization of the central trigeminovascular neurons. In migraine, nociceptor stimulation on the dura activates the second sensory neurons in the trigeminal nucleus caudalis (TNC). Migraine that is associated with allodynia is mediated by sensitization of the TNC neurons. Triptans cannot abort (ie, render pain-free) migraine when there is ongoing allodynia, nor can they block central sensitization that has become activity-independent (ie, independent of incoming impulses from the periphery).
The researchers attempted to determine whether cyclooxygenase (COX)-1/COX-2 inhibition can block ongoing sensitization of the peripheral and central trigeminovascular neurons and to identify sites of action along the trigeminovascular pathway in a rat model of migraine. Using single-unit recording, they tested whether naproxen infusion (0.4 mg/kg) can block ongoing sensitization in the peripheral and central trigeminovascular neurons that was induced hours earlier by topical application of inflammatory soup on the dura. Sensitization was assessed with changes in spontaneous activity, responses to mechanical and thermal stimuli, and expansion of receptive fields. Using immunocytochemical techniques, they mapped the distribution of COX-1 and COX-2 enzymes in the dura, trigeminal ganglion, and spinal trigeminal nucleus. They found that the infusion of naproxen blocked sensitization in the meningeal nociceptors and suppressed ongoing sensitization in the spinal trigeminal nucleus. This inhibitory action was reflected by normalization of the neuronal firing rate and attenuation of neuronal responsiveness to mechanical stimulation of the dura, as well as mechanical and thermal stimulation of the skin. COX-1 was found in endothelia cells along the dural blood vessels and in the dorsal horn neurons and glia cells. COX-2 was found in the meningeal macrophages, trigeminal ganglion neurons, lamina V neurons, and glia cells. The naproxen suppression of ongoing central sanitization suggests that spinal cyclooxygenases promote the shift from activity-dependent to activity-independent central sensitization during migraine. Parenteral administration of COX-1/COX-2 inhibitors may therefore be appropriate rescue therapy for patients seeking emergency care for migraine.
Results from the study by leagues suggested that pharmacotherapy that concurrently targets serotonin dysmodulation and inflammation in migraine may improve outcomes over monotherapy. A short-acting triptan and a long-acting nonsteroidal anti-inflammatory drug (NSAID) may also provide additional benefits over either one alone.
Silberstein and colleagues evaluated the efficacy and tolerability of sumatriptan formulated with RT TechnologyTM 85 mg (SumaRT) and naproxen sodium 500 mg (Nap), a unique fixed-dose, single-tablet formulation (SumaRT/Nap) vs the individual drug components. They performed 2 identical randomized, double-blind, placebo-controlled, parallel group, single-attack (moderate/severe), multicenter studies of adult migraineurs: Patients received SumaRT/Nap, sumatriptan 85 mg RT (SumaRT), NAP 500 mg, or placebo. Efficacy endpoints included relief of pain and associated symptoms at 2 (coprimary endpoint) and 4 (secondary endpoint) hours. Comparisons between treatment groups were formulated with a hierarchical step-down method to control for multiplicity.
All efficacy results described here in the study were statistically significant. All treatments were well tolerated, and the adverse event profile of SumaRT/Nap was similar to each of the two components, sumatriptan and naproxen sodium. SumaRT/Nap, which targets multiple mechanisms, demonstrates superiority for standard endpoints without an increased incidence of adverse events when compared with monotherapy.
Symptoms, such as lethargy, yawning, mood changes, nausea, neck stiffness, and tiredness, are reported in the migraine prodrome and may reflect involvement of dopaminergic pathways. Scientisits set out to identify dopamine receptor subtypes in the trigeminocervical complex (TCC) and explore the effects of dopamine on second-order trigeminal neurons.
Dopamine receptors were found to be present in the TCC. Cell firing was strongly and reversibly inhibited by microiontophoretic application of dopamine in a dose (current)-dependent manner . The study authors concluded that dopamine receptors are located in the TCC, activation of which produces inhibition of neuronal activity. These data may provide insight into the mechanisms that are involved in the premonitory phase of migraine.
The new International Classification of Headache Disorders (ICDH-II) distinguishes subtypes of chronic daily headache (CDH), especially chronic migraine (CM) and medication overuse headache (MOH). CM is a new entity defined by migraine headaches on 15 or more days per month for 3 or more months in the absence of medication overuse (MO). If MO is present, the diagnosis of MOH is made, as long as the headache developed or worsened with MO.
What is the mechanism of MOH? Opioids paradoxically produce hypersensitivity to evoked nonnoxious stimuli (ie, allodynia) in humans and in rodents. In rats, sustained morphine induces hindlimb allodynia and enhances evoked release of pronociceptive neurotransmitters. King and colleagues hypothesized that morphine treatment would elicit similar actions in trigeminal afferents and in the medullary dorsal horn. These effects might serve as a model to study mechanisms of MOH. King and colleagues therefore conducted experiments designed to determine whether sustained, systemic morphine administration elicits neuroplastic, pronociceptive adaptations in the trigeminal system as a potential model to study mechanisms of morphine overuse headache.
Migraine pain is often associated with facial allodynia in humans. In rats, sustained morphine produced facial allodynia, increased responsiveness of trigeminal afferent fibers, and increased activation of neurons in the medullary dorsal horn. The increased facial sensitivity was readily reversed by drugs known to be efficacious in human migraine pain, suggesting that the neuroplastic adaptations elicited in the trigeminal system by sustained morphine exposure may serve as a model to study the mechanisms of MOH.
Migraine treatment can be acute or preventive. Preventive treatments are designed to reduce the frequency, duration, or severity of attacks. Observational studies have demonstrated that patent foramen ovale (PFO) closure in patients with stroke and decompression sickness leads to migraine resolution in 65% to 90% of patients. The MIST (Migraine Intervention with STARFlex Technology) trial was the first trial to attempt to investigate these observations with a prospective, double-blind, placebo-controlled design.
Patients aged 18-60 years who had migraine with aura (according to International Headache Society 1988 classification) that was refractory to 2 or more classes of prophylactic medications and who had a minimum of 5 migraine headache-days and 7 headache-free days per month were recruited. Transthoracic contrast echocardiography was used to detect right-to-left shunts and to semiquantitatively assess their size. Patients with a moderate- or large-size PFO were randomized to PFO closure with the STARFlex septal repair implant or to a sham procedure. Daily headache diaries were completed during a baseline evaluation and throughout the follow-up period. Patients and their headache specialists remained blind to randomization during the 180-day follow-up period. Four hundred thirty-two patients were recruited and screened for shunts. Two hundred sixty (60.2%) patients had a shunt, and of these, 163 (37.7% of total patients and 62.7% of those with shunts) had a moderate or large PFO. Of the patients with a moderate or large PFO, 16 withdrew or were withdrawn for medical reasons before randomization.
The results from the diagnostic phase of the trial confirmed previous studies showing that moderate or large right-to-left shunts (mostly PFOs) are very common in patients who have migraine with aura. The prevalence of moderate or large shunts (mostly PFOs) is about 6-fold greater in the trial population than in the general population. The MIST trial did not reach its primary endpoint. The degree of closure of the shunts was not reported nor were results for the additional endpoints.
During this year's AAN meeting, a number of important studies were presented about headache and migraine. Results from studies on risk factors for migraine, allodynia and migraine, triptans in combination with NSAIDs for migraine, migraine premonitory symptoms and dopamine, FHM, MOH, and preventive migraine treatment, and their implications, were summarized.
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