Neuromodulation Devices in Migraine: The Latest

Migraine is a neurobiological disease characterized by episodic disabling attacks of moderate to severe head pain, associated with nausea and/or vomiting and light or sound sensitivity; it affects up to 12% of the US population. Untreated, attacks reduce an individual’s ability to function, creating a significant impact on work and family activities. Treatment to abate attacks is required by most patients, though studies show that only a portion of patients take medications to treat migraine attacks]. Up to 40% of people with migraine would benefit from additional treatment to reduce the frequency of migraine—ie, a preventive—but studies show that only 13% of people in the United States use migraine prevention measures. Treatment options for migraine vary from over-the-counter medications to prescription treatments. Prescription medications are often stopped due to lack of tolerance and poor efficacy as stated by patients.

Neuromodulation is a technique that employs stimulating the nervous system via electric currents or a fluctuating magnetic field to modulate pain pathways. This type of treatment can have an immediate effect, making it useful for aborting migraine attacks. Daily scheduled use can modulate the nervous system and allow for a preventive effect. Numerous devices have been studied for the acute and preventive treatment of migraine. They offer patients an option that is well tolerated and may be used for both acute and preventive needs in migraine. Here is an overview of available devices approved by the US Food and Drug Administration (FDA).

The Latest FDA-Approved Neuromodulation Devices

STS
Transcutaneous supraorbital nerve stimulation (STS), also known as Cefaly, was first studied as a preventive option in episodic migraine patients, with findings of reduction in headache days in participants with migraine. A larger study was conducted, showing that once-daily use of the device for 3 months resulted in 30% reduction in migraine days in the active group. The most frequent adverse event was paresthesia in the area of stimulation; it was mostly mild and reversible, although some participants found it intolerable.

STS has also been found effective for the acute treatment of migraine in a randomized controlled trial. An open-label trial of the use of STS for the prevention of chronic migraine has also shown reduction in headache days over 4 months with use of STS for 20 minutes per day.

sTMS
Single-pulse transcranial magnetic stimulation (sTMS) is delivered with a hand-held device that creates a fluctuating magnetic field which triggers an electric current that modifies cortical excitability. In the United States, it was first FDA-approved for acute use in patients with migraine with aura, based on a randomized controlled trial showing higher pain-free rates at 2 hours in the treatment versus sham group. A multicenter, open-label US study has shown sTMS to be beneficial in the prevention and acute treatment of episodic and chronic migraine. Treatment is well tolerated, with limited adverse events reported.

nVNS
Noninvasive vagal nerve stimulation (nVNS), commercially available as gammaCore, is known to be helpful in epilepsy and depression. It was incidentally noted that patients receiving invasive VNS were reporting reduced migraine attacks, though the mechanism for this is still unclear. nVNS has been FDA-approved for the acute treatment of episodic migraine. A randomized controlled trial of nVNS for the treatment of migraine attacks showed that it was well tolerated and produced higher pain-free and pain-relief rates at 2 hours compared with sham stimulation. It was also shown to have reproducible effects when used for multiple migraine attacks.

Limitations of Neuromodulation

There are multiple challenges that should be noted when evaluating the evidence for neuromodulation in the treatment of migraine. Studies were conducted on a relatively small number of participants. Using these results to generalize to a larger, less homogeneous population can be difficult. Maintaining blinding is another limitation of studies of neuromodulation; it is difficult to design a placebo-controlled study when you are using a device that may produce paresthesia. Sham devices need to produce some effect, but not significant enough to produce an improvement in symptoms. This could lead to difficulty maintaining blinding and lead to lower or higher placebo efficacy rates, depending on the sham device.

Cost may also be a challenge. At this time, there is limited insurance coverage for these devices in migraine. And while many devices have shown benefit in improving quality of life over time, which may possibly be translated to fewer missed work days and less need for prescription acute medications, it is often difficult for patients to take on direct costs at once.

While there are several challenges, neuromodulation can be a beneficial addition to a patient’s regimen. Patients who are overusing acute medications, patients who would like to limit the use of oral medications, or patients who have a partial response to therapeutic agents either for acute or preventive treatment are particularly good candidates for the use of neuromodulation. In clinical practice, neuromodulation is often used in women who are pregnant. Though not FDA indicated, it is considered safe, and patients often feel comfortable having an option that does not involve medications.

In conclusion, while studies showing beneficial effect of neuromodulation devices are small, they seem to indicate an improvement in severity of attacks and quality of life, and the possibility of improvement in frequency of attacks, with limited adverse events. At this time, it is difficult to determine cost/benefit for patients with migraine, and these considerations should be discussed when considering the use of neuromodulation in migraine.

Called Cefaly, the Belgian-made device is the first to win FDA approval for migraine prevention and is also the first transcutaneous electrical nerve stimulation (TENS) system OK’d for any type of pain prevention, as opposed to acute treatment, the agency said.

The device is battery-powered and worn around the head, with the actual TENS stimulator centered on the forehead just above the eyes. It delivers a small, steady current to trigeminal nerve branches. Patients will be instructed to use the device once daily for a maximum of 20 minutes. It is approved for adults only.

Approval was based primarily on the PREMICE trial, in which 67 adult patients were randomized to wear either the Cefaly device or a nonfunctional sham. When turned on, the device typically causes a tingling sensation, but the trial investigators sought to maintain blinding by not asking participants what it felt like and by trying to keep them from talking with each other.

Patients assigned to the real device showed a decline from baseline of about two headache days per month, compared with no change in the control group. A responder analysis showed that 38% of patients receiving stimulation had at least a 50% reduction in monthly headache days, compared with 12% of the control group.

The Cefaly device was previously approved in Europe and Canada. The device’s manufacturer, STX-Med of Herstal, Belgium, submitted results of a patient satisfaction survey conducted among more than 2,000 users in Europe, indicating that most regular users believed they had experienced “very significant improvement” and only 4% reported adverse effects.

Across the entire respondent group, including those who only used the device infrequently or not at all, 54% reported substantial improvement.

Complaints about the device included dislike of the tingling sensation, sleepiness during the treatment sessions, and headache following the sessions, the FDA said. None of the reported adverse effects were considered serious.

Numerous TENS devices are already marketed for pain treatment.

White matter brain lesions appeared 68% more often in migraineurs with aura than in those without migraine; a trend for 34% elevated risk of white matter in migraine patients without aura didn’t reach significance, Messoud Ashina, MD, PhD, of the Danish Headache Center at Glostrup Hospital in Copenhagen, and colleagues found.

Clinically-silent infarct-like abnormalities and brain volume changes also correlated with migraine, they reported online in Neurology.

However, it’s still not clear how these changes arise or whether they have any clinical significance, the group cautioned. “Traditionally, migraine has been considered a benign disorder without long-term consequences for the brain,” they noted.

MRI imaging to exclude secondary causes of headache often turns up such abnormalities that worry both neurologists and patients, the group noted.

“Patients with white matter abnormalities can be reassured,” they recommended. “Patients with infarct-like lesions should be evaluated for stroke risk factors. Volumetric MRI remains a research tool.”

Eli Feen, MD, a neurologist at Saint Louis University in St. Louis, agreed with the researchers on evaluating stroke risk factors in patients with infarct-like brain lesions on MRI. But he suggested it should be done regardless of migraine status, and instead be based on age and the prevalence of stroke.

“What is reassuring is that when we look at the brain MRI of a migraine patient, we don’t have to be concerned about the lesions or abnormalities of the white matter suggesting something more malignant,” he said in an interview.

Without knowing the true clinical significance of the findings, clinicians should focus on making sure that migraine is taken seriously and treated properly, commented Emily Rubenstein Engel, MD, associate director of the Dalessio Headache Center at Scripps Clinic in San Diego.

“It is a disease that can — and should — be managed well, so that patients are minimally symptomatic and have minimal injury to their brain,” she said in an email to MedPage Today.

But while there’s growing evidence that migraineurs are at slightly elevated stroke risk overall, there’s no evidence that preventing migraine reduces that risk, argued Andrew Charles, MD, director of the headache research and treatment program at the University of California Los Angeles.

“Patients with migraine, particularly those with aura along with their migraine attacks, should work to reduce other stroke risk factors like high blood pressure, high cholesterol, and smoking,” he suggested in an email to MedPage Today.

The meta-analysis included six population-based studies and 13 clinic-based studies that looked for MRI abnormalities in migraineurs from 1989 through 2013.

The prevalence of white matter abnormalities ranged from 4% to 59% across the studies.

Pooled analysis of the four that reported on this measure indicated an odds ratio of 1.68 for migraine with aura compared with no-migraine controls (95% CI 1.07-2.65).

The odds of white matter lesions was 1.34 for migraine without aura but missed statistical significance (95% CI 0.96-1.87).

One of the studies, CAMERA-2, suggested no link between white matter abnormality progression and anti-migraine therapy; another indicated no increased risk of stroke, heart attack, or cardiovascular death with triptan medication.

“While this result is reassuring, robust conclusions are limited due to confounding by indication,” Ashina’s group cautioned.

For silent infarct-like lesions, the likelihood across two pooled studies was 44% higher for migraineurs with aura than without aura (P=0.04), but no statistically significant association emerged for either compared with controls.

“It is unclear whether silent infarct-like lesions predispose to or are associated with development of clinical stroke,” the researchers pointed out.

Also, whereas infarct-like lesions are associated with cognitive decline and dementia in the elderly, CAMERA-2 and another study didn’t show a link to cognitive decline in migraine and other severe types of headache, they added.

Theories are that these lesions could represent a combination of episodic focal brain under-perfusion or a manifestation of hypertensive small-vessel disease.

Of the nine studies that looked at brain volume, seven indicated reduced grey matter density in brain regions in migraineurs compared with controls. Another study indicated increased grey matter density in the periaqueductal gray (a region involved in pain processing) and the dorsolateral pons regions only in migraine with aura.

“Additional longitudinal studies are needed to determine the differential influence of migraine without and with aura, to better characterize the effects of attack frequency and to assess longitudinal changes in brain structure and function,” the group concluded.

Limitations included heterogeneity in patient samples, selection criteria, headache characteristics, test methodology, timing, and data interpretation, as well as the possibility of residual or unmeasured confounding and unclear directionality of associations.

The study was supported by the Lundbeck Foundation and the Novo Nordisk Foundation.

Ashina reported being an associate editor of Cephalalgia and a consultant or scientific adviser for Autonomic Technologies, Allergan, Amgen, and Alder.

The results are significant in terms of understanding the neurobiology of migraine and could have future implications for drug treatment, said study author Peter James Goadsby, MD, PhD, professor, neurology, and director, Headache Program, University of California at San Francisco, and president, International Headache Society.

“This is an important step in solidifying our ideas that migraine is fundamentally a disorder of the brain, not a disorder of structures outside the brain,” said Dr. Goadsby. “We were able to address the question that people have wondered about for many, many years, that is, what is the degree to which pain is driving the initial symptomatology — and we got clear answers to that.”

Dr. Goadsby and his colleagues won the Harold G. Wolff Lecture Award for this research during the 2013 International Headache Congress (IHC).

Subtle Symptoms

Premonitory symptoms of migraine can include yawning, neck discomfort, nausea, thirst, photophobia, phonophobia, craving sweet or savory foods, and mood swings. It’s not clear what proportion of patients with migraine experience these early symptoms, which are often quite subtle, Dr. Goadsby said. Estimates vary widely, from about a third to 80%.

In the past, this symptomatology has not received much medical attention, said Dr. Goadsby. Physicians might not ask about premonitory symptoms because this information doesn’t influence their diagnosis.

In years gone by, people used to think of migraine as a disorder of the blood vessels. In more recent times, the view has been that migraine is a reaction to pain stimuli. “I think our new research suggests that this is just not true,” said Dr. Goadsby.

Using nitroglycerin, a well-documented trigger for migraine, researchers induced premonitory symptoms in patients who have migraine without aura. Instead of waiting for headache onset to begin scanning the patients’ brains, as has been done in the past, researchers did the scanning during the premonitory phase. Eight patients had at least 1 premonitory scan without pain.

“Before this, all the imaging of migraine has been during the headache and the question has risen as to the degree to which what’s happening in the brain is just a response to pain, or is something more fundamental, a part of the process of the migraine,” said Dr. Goadsby. “By studying the premonitory symptoms, you get rid of that question because these patients don’t have any pain.”

Neuronal Activation

Researchers used H₂ ¹⁵O (radioactive water) to measure regional cerebral blood flow as a surrogate marker for neuronal activation.

They found that compared with baseline scans, there was activation in several key areas, including the hypothalamus, an area involved in low-level regulation of sleep, appetite, mood, and fluids. “It seems likely that the hypothalamus is pivotal in the onset of migraine,” commented Dr. Goadsby.

Other structures that were activated included the midbrain, around the periaqueductal grey, which has been shown to be active during a migraine attack, and an area in the pons that past migraine imaging has also shown to be active.

“This shows you the areas of the brain that are involved at the earliest in the attack,” said Dr. Goadsby.

Scans of the 8 patients plus another 2 patients experiencing photophobia symptoms, again before they felt any pain, showed activation in the visual cortex. “This suggests that the photophobia experience can be dissected away from the pain experience,” said Dr. Goadsby.

Similarly, scans of patients experiencing nausea had activation of an area of the medulla that includes nausea and vomiting centers. “So it’s entirely plausible that those areas are activated by the migraine process and that’s why nausea and vomiting are so common in migraine; it’s not simply a response to the pain,” said Dr. Goadsby.

“It was thought that nausea and pain were highly linked, but that doesn’t seem to necessarily be the case,” he added.

Dr. Goadsby hopes the research will “shift thinking” to consider migraine as a brain disorder, but he stressed that this should not lessen the importance of the pain that migraine patients suffer.

The research could have ramifications for treatment in that the most obvious target would be the brain, but developing targeted therapies that don’t have adverse effects could be challenging.

“From a big picture treatment perspective, this says to me that we probably won’t get away with developing drugs that don’t get into the brain to have substantial effects on migraine prevention,” said Dr. Goadsby.

He noted that to date, the best proven migraine prevention therapies are anticonvulsant drugs, tricyclic antidepressants, and the β-blocker propranolol, all of which affect the brain. This, he said, is consistent with the theory that migraine is a disorder of the brain.

Original Article

The prophylactic effect – a reduction in cluster attack frequency, but in most cases without acute pain relief – came as a surprise to investigators in the prospective, controlled, multinational Pathway CH-1 study, Dr. Jean Schoenen admitted at the European Headache and Migraine Trust International Congress.

“This was the largest, most rigorous study to date of an implantable medical device for headache treatment. The study was not designed to look at attack frequency; it was designed to look at acute response. Yet, we have this preventive effect that I think now has to be confirmed in another well-designed trial,” said Dr. Schoenen, coordinator of the headache research unit at the University of Liege (Belgium).

For more than 100 years, the sphenopalatine ganglion (SPG) has been thought to be a key mediator of the cranial autonomic symptoms and unilateral periorbital pain that define cluster headaches. In the Pathway CH-1 study, Dr. Schoenen and coinvestigators evaluated the efficacy and safety of a miniature electrical neurostimulator implanted in the pterygopalatine fossa near the SPG. The neurostimulator is activated by a hand-held remote controller the patients hold up to their face for on-demand therapy.

A neurosurgeon implants the SPG neurostimulator via a minimally invasive procedure using a transoral, gingival buccal technique that leaves no externally visible scars.

Dr. Schoenen reported on 28 chronic cluster headache patients who were dissatisfied with their current treatment and opted to participate in the trial. They underwent neurostimulator implantation, followed by a minimum 3-week postsurgical stabilization period during which the device remained switched off. During the subsequent controlled experimental phase, they each self-treated a minimum of 30 attacks over a 3- to 8-week period. Once the device was fired up, it couldn’t be employed again for 90 minutes. The remote controller was programmed to randomly deliver full stimulation, subthreshold stimulation, or sham treatment.

Overall, 7of the 28 patients, or 25%, were categorized as acute responders, meaning that full stimulation achieved marked pain relief within 15 minutes with no acute medication in more than half of treated attacks. Another 10 patients (36%) were “frequency responders” who experienced at least a 50% reduction in cluster attack frequency, compared with baseline with no change in preventive medications and with nonacute pain relief. Two patients (7%) were both acute and frequency responders. A total of 32% were nonresponders.

Frequency responders didn’t start experiencing fewer cluster attacks until after the weeks of postsurgical stabilization ended and neurostimulation began. This makes it highly unlikely that the prophylactic effect was somehow due to the surgery itself, according to the neurologist.

Significant pain relief was documented 15 minutes after full stimulation in 67% of treated attacks, half of which involved pain freedom. In contrast, significant pain relief occurred in only 7% of attacks that were addressed with subthreshold stimulation or sham treatment.

Sixty-four percent of subjects showed clinically meaningful and statistically significant reductions in headache disability as indicated by improved scores on the Headache Impact Test-6. Quality of life improved in 75%, as reflected by their scores on the Short Form-36 physical and/or mental component summary scores, Dr. Schoenen continued.

Acute medications were used within 90 minutes of 31% of cluster attacks treated with full stimulation, compared with 78% of those addressed using subthreshold stimulation and 77% that got sham therapy.

Far and away, the most common adverse event involved mild-to-moderate sensory disturbances in the maxillary division of the trigeminal nerve, experienced by 81% of subjects. These symptoms resolved within 3 months. Two patients experienced infections. Two others required device explantation due to lead migration.

The ongoing Pathway CH-1 study will continue on an open-label basis for 1 year post-implantation.

The device, known as the ATI Neurostimulation System, is MRI compatible. It has been approved for marketing by the European regulatory authorities. The manufacturer, Autonomic Technologies of Redwood City, Calif., will also seek Food and Drug Administration approval.

In addition, the company has launched the multicenter, controlled European Pathway M-1 trial in which SPG neurostimulation is being evaluated for the treatment of disabling migraine.

Dr. Rigmor H. Jensen, president of the European Headache Federation, commented that an invasive device such as this will likely be reserved for those few cluster headache patients who are completely refractory to all medications. That’s probably 1%-3% of the cluster headache population, estimated Dr. Jensen, research professor of neurology at the University of Copenhagen.

Dr. Schoenen is a consultant to Autonomic Technologies, which is funding the Pathway CH-1 study.

By: BRUCE JANCIN, Clinical Neurology News Digital Network

The unbalanced levels of the neurotransmitters (dopamine and noradrenaline) and neuromodulators (eg, tyramine, octopamine, and synephrine) in the synaptic dopaminergic and noradrenergic clefts of the pain matrix pathways may activate, downstream, the trigeminal system that releases calcitonin gene-related peptide. This induces the formation of an inflammatory soup, the sensitization of first trigeminal neuron, and the migraine attack. In view of this, we propose that migraine attacks derive from a top-down dysfunctional process that initiates in the frontal lobe in a hyperexcitable and hypoenergetic brain, thereafter progressing downstream resulting in abnormally activated nuclei of the pain matrix.

Introduction

Migraine is a disabling condition characterized by unilateral headache pain, pulsating in quality and lasting 4–70 hours, accompanied by photo-, phono-, osmo-phobia, nausea, and vomiting. Aura may precede the migraine attacks in about 30% of patients and, in some patients, occurs as an isolated symptom.^[1] The etiology of migraine is still not completely understood. This is because of the multiple complex symptomatology characteristic of migraine (headache attacks and psychiatric, neurologic, and sympathetic symptoms) and difficulty in unifying these characteristics into one or more interelated pathophysiological processes.

A pathophysiological hypothesis that may reconcile with the proteiform symptomatology of migraine has been proposed by Welch. According to this hypothesis, migraine is a multifactorial (ie, biological and psychological) biobehavioral disorder^[2] in which the crisis is a response to stressful agents within an hyperexcitable brain.^[3] Genetic mutations and/or polymorphisms of genes, yet to be determined, that regulate neuronal mitochondrial energy, neurotransmitter metabolism, and ion channels in the central nervous system (CNS) are considered the main biological factors.^[4] Menstrual cycle, pregnancy, lifestyle, diet, anxiety, chronic stress, etc, are among the main psychological factors.^[5] Once the migraine threshold is primed, the frequency of the attacks depends on the type of stress and anomalies in the metabolism of neurotransmitters and neuromodulators that regulate the synapses of cortical, antinociceptive (antinociceptic system [ANS]), and sympathetic neurons.^[6]

In the CNS, glutamic acid and aspartic acid are the main excitatory neurotransmitters, whereas gamma aminobutyric acid (GABA) is the inhibitory neurtransmitter.^[7] The balance between these 2 systems constitutes the frame in which the other circuitries regulate the functions of the human brain. It has been hypothesized that anomalies in the metabolism of glutamate and GABA, together with those that govern pain and vegetative functions, such as serotonin (5-HT), dopamine (DA), and noradrenaline (NE), constitute the phenotypical biochemical causes of the migraine.^[8]

Recent evidence also supports the old notion that elusive amines, such as tyramine (tyr) and octopamine (Oct), play a role in migraine pathogensis.^[9] These amines, together with DA and NE, are products of two different metabolic pathways of tyrosine. Tyrosine hydroxylase generates 3,4-dihydroxyphenylalanine (DOPA), DA, and NE, with the last 2 compounds requiring the action of DOPA decarboxylase and dopamine β-hydroxylase (Dβ-H) enzymes, respectively. The alternative pathway, tyrosine decarboxylase, synthetizes tyr, Oct, and synephrine, with Oct and synephrine requiring in addition Dβ-H and phenylethanolamine-N-methyltransferase (PNMT) enzyme activities^[10] (see the Figure). Although the hypothesis that tyr and Oct may contribute to pathogenesis of migraine was proposed several decades ago,^[11] the recent discovery of a new class of G-protein-coupled receptors with high affinity for these amines in rodents and humans has fuelled ever-increasing scientific interest. The trace amine receptors (TAARs) are found in various tissues and organs, including specific brain areas such as the rhinencephalon, limbic system, amygdala, hypothalamus, extrapyramidal system, and locus coeruleus.^[12] This and other evidence has led to the suggestion that tyr and/or Oct behave as neurotransmitters and neuromodulators via TAARs and other receptors (eg, catecholaminergic receptors), respectively, contributing to physiology of noradrenergic and dopaminergic synaptic transmission in the ANS.^[13]

We hereby summarize briefly the results, mainly generated from our laboratory, that support a role for biochemical alterations of different neurotransmitters and neuromodulators in the pathophysiology of migraine. Based on this evidence, we propose that future research efforts aiming to comprehend the pathophysiological relevance of neuromodulators, such as trace amines, in the CNS, have the potential to provide for new, more effective, treatment options for migraine.

Excitatory Amino Acids and Aura

The aura constitutes the clinical phenotype of migraine with aura. The hypothesis that aura is a clinical counterpart of a cortical phenomena derives from the observation of Lashley’s own visual phenomena.^[14] The speed of the scotomata on the visual field, 3 mm/minute, and the fundamental studies of Olesen and his group on cerebral blood flow (CBF), in patients during their auras, have substantially demonstrated that the spreading depression (SD) of Leao is the neurophysiological cortical event of the aura symptomology. In these human experiments, the positive scotomata (visual scintillations and/or paresthesia) is concomitant to a brief increase in blood flow, and the negative symptoms to a reduced flow (oligemia) that propagates at the speed of 3 mm/minute on the occipital cortex.^[15] Studies with functional magnetic resonance imaging (MRI), during spontaneous aura, have confirmed that the first phase of the aura is accompanied with a brief focal occipital increase in the brain oxygen-level dependent (BOLD) signal that propagates at the same velocity of SD on the occipital cortex, followed by a longer lasting decrease and impaired BOLD response to functional activation.^[3] The clinical picture and the features derived from CBF and functional MRI (fMRI) studies suggest that the positive and negative signs of the aura may be caused, as in SD, by a burst of activity followed by suppression of neuronal cortical activity.

We hypothesized that neuronal hyperexcitability constitutes the functional prerequisite of the occurrence of the aura.^[3] An array of biochemical, neurophysiological, and pharmacological data in humans support this hypothesis. Glutamate, released from neurons and glia, is the main excitatory neurotransmitter in the CNS. Anomalous levels of glutamic acid determine SD in animal experiments and ingestion of glutamate-rich food provokes, in predisposed subjects, migraine attacks.^[16,17] To date, it is almost impossible to directly measure glutamate levels in the human brain. Platelets, however, have constituted a valid model to study glutamate metabolism because these cells display glutamate-related components similar to those of the neurons. A number of studies, conducted in the last 2 decades, have demonstrated that the levels of glutamic and aspartic acids are significantly more elevated in platelets, plasma, and CSF of migraine patients, particularly in those with aura.^[18–20]

Occurrence of CNS hyperexicitability in migraine is also supported by neurophysiological studies employing transcranial magnetic stimulation (TMS). Stimulation with TMS of the occipital lobe in migraine with aura patients determines the appearance of a higher number of phosphenes in comparison with control and migraine without aura sufferers.^[21] These same results were also found stimulating the motor areas and measuring the resting motor threshold and the silent period.^[22] Although the authors suggest that these response abnormalities are due to a reduced inhibitory cortical tone,^[23] the possibility that an increase in glutamate levels in the CNS plays a major role in pathogenesis of the aura is supported by ^[31]pNMR studies and pharmacological evidences employing lamotrigine. In comparison with control subjects, the levels of magnesium, measured with ^[31]pNMR, are significantly lower in the brain of migraine patients, particularly during the painful attacks.^[24] Magnesium is a unique compound known to block glutamate-dependent SD.^[25] Lamotrigine is an antiepileptic drug useful in the prevention of partial and generalized seizures as well. It acts by blocking voltage-sensitive channels leading to an inhibition of neuronal glutamate release.^[26] Based on these pharmacodynamic characteristics, we conducted an open pilot study aiming to assess the effects of lamotrigine in migraine with aura. Twenty-five migraine patients with high frequency of aura attacks (at least 2 auras/month) were treated for 2 months. There was a dramatic reduction in the aura frequency and duration in the treated patients. Thereafter, a number of studies have confirmed the efficacy of lamotrigine in the prevention of auras.^[27,28] The specificity of this drug for the prophylaxis of the migraine aura is stressed by the inefficacy of lamotrigine in the reduction of migraine without aura attacks^[29] and the capacity of lamotrigine, in contrast to valproate, to block the SD-induced by potassium cloride (KCl) on the rat occipital cortex.^[30]

Elusive Amines, Premonitory Symptoms, and Migraine Attack

The modalities by which stressful agents within the brain may cause the painful attacks in migraine is not known; however, according to the theory put forth by Welch, the first pathophysiological event may occur in the orbitofrontal part of the frontal lobe and, thereafter, downstream to the limbic, amygdale, and hypothalamic-connected areas of the CNS. Although still partly speculative, an increasing body of clinical, biochemical, and functional studies now support this theory. Migraine attacks are, very often, preceded by premonitory symptoms, such as hyperosmia, yawning, mood changes, anxiety, food craving, sexual excitement, fatigue, and emotional lability, which last from minutes to days.^[31,32] These symptoms are considered markers of activation of the above-mentioned brain areas, and, therefore, it is logical to attribute the first phase of the migraine attacks within these areas.^[33] Further support also derives from evidences showing that, in these same brain areas, TAARs and dopamine receptors are abundantly distributed. The activation of these receptors is likely reflected in the high levels of dopamine and elusive amines found in plasma and platelets of migraine without aura sufferers during headache-free periods.^[34,35]

Catecholamines, Elusive Amines, and the Migraine Attack

After the premonitory symptoms in migraine, the painful phase occurs. One current hypothesis considers the head pain a consequence of trigeminal activation. This determines release of the neuropeptides, calcitonin gene-related peptide (CGRP) and substance P (SP), in the trigemino-vascular system.^[36] Both peptides stimulate platelets, leukocytes, and endothelium to secrete an inflammatory soup (5-HT, adenosine diphosphate [ADP], platelet-activating factor, nitric oxide [NO], interleukins, etc) that sensitizes the first-order neuron of the trigeminal system and, after minutes or hours, the second, by an early gene-related process in the nucleus.^[37]

The pathophysiological process that underlies trigeminal activation is a debated question. One hypothesis, derived from studies performed in animal models, suggests that the wave of the SD on the occipital cortex stimulates the nerve endings of the trigeminal system surrounding the pial vessels. This stimulation determines a trigeminal antidromic reflex resulting in the release of CGRP and SP in the dura mater head circulation. CGRP has been long suggested to be important in the occurrence of headache attacks because of its capability to interact with circulating cells and to determine neurogenic inflammation. CGRP stimulates platelets, white cells, and endothelium to synthesize NO. NO is considered a diffusible neurotransmitter in the CNS and, as such, may play a role in the release of glutamate and diffusion of SD on the cortex. In the circulation, it is a potent vasodilatator. NO, while dilatating the vessel wall, stretches the trigeminal endings innervating the wall, already sensitized by the inflammatory soup, and determines the migraine attack.^[38]

Another hypothesis, and not mutually exclusive, is that the activation of the trigeminal system is a result of abnormal pain processing initiating in the frontal lobe and, thereafter, progressing downstream to the connected pain centers.^[2,39] In support of this hypothesis is a functional fMRI study showing that inhibition of the orbito-frontal cortex, an important pain inhibitory cortex area, occurs in chronic migraine when the pain subsides.^[40] Also, evidence from fMRI and PET studies have shown activation of the red nucleus, extrapyramidal system, and nuclei behind the aqueduct of the brain stem before and during migraine attacks,^[41,42] all parts of the descending centers of the pain matrix. The modalities and the characteristics of the activation of these nuclei, however, are not known.

We hypothesized that abnormal levels of elusive amines and catecholaminergic neurotransmitters such as DA and NE, all products of tyrosine metabolism, play an important role in the pathophysiology of migraine attacks.^[34] As mentioned previously, TAARs are located in the rhinencephalon, limbic system, amygdala, hypothalamus, extrapyramidal system, and locus coeruleus. These areas are important parts of the pain matrix that modulates the pain threshold.^[39] The functions of the pain matrix neurons are mainly regulated by synapses that utilize DA and NE as neurotransmitters. Intriguingly, the highest levels of Oct are found in the same brain regions.^[43] Oct acts, in the same synaptic clefts, as a neuromodulator. A neuromodulator is a chemical released from a neuron that causes no change in the excitability of the postsynaptic cells in the absence of a neurotransmitter. The released neuromodulator acts to modify the action (increase or decrease) of a coexisting neurotransmitter.^[14] Thus, one possible physiologic role Oct is to regulate, together with other neurotransmitters, DA and NE synapses in the centers that regulate the pain threshold. As hypothesized by Welch, it is possible that, in the particular metabolic circumstances such as that associated with migraine, there occurs an abnormality in the metabolism of tyrosine toward increased synthesis of products of the decarboxylase pathway, resulting in increased synthesis of tyr, Oct, and synephrine in association with a decrease of NE. In support of this, we recently demonstrated that there occur higher levels of circulating Oct and synephrine along with increased levels of DA in migraine without aura (MwoA) patients, in comparison with healthy controls subjects.^[44] The higher levels of DA are suggestive of a reduction in dopamine Dβ-H enzyme activity. Reduced Dβ-H enzyme activity^[45] and reduced NE levels have been reported in migraine without aura patients.^[46] Also, more recently, a polymorphism in the gene that encodes for Dβ-H protein has been identified.^[47] All these results support the possibility that complex abnormalities in the metabolism of tyrosine-related pathways occurs in migraine patients, resulting in possible derangement in neurotransmitters and neuromodulators. If the same biochemical anomalies found in the circulation of migraine sufferers are present in the synaptic clefts innervating the pain matrix, an unphysiologic balance between neuromodulators (Oct and synephrine) and neurotransmitters (DA and NE) the intra-synaptic milieu should be expected. Possible pathological consequences include abnormal function of the hypothalamus,^[33] the sympathetic system with related autonomic symptoms, reported in migraine patients (eg, orthostatic blood pressure changes, anomalies of pupillary control, and vertigo),^[48] and the ANS nuclei, with downstream activation of the trigeminal nucleus, CGRP release in the encephalic circulation and head pain. Another possibility is that cortical SD may direct activate second-order trigeminovascular neurons, as recently suggested by Lambert et al^[49] employing animal models. However, the biochemical pathway(s) involved in this process is (are) still unknown.

Biochemical Tryptophan Anomalies and Painful Attacks

The main product of tryptophan hydroxylase is serotonin (5-HT), whereas tryptamine is the neuromodulator that derives from the decarboxylase product of tryptophan. The involvement of 5-HT in migraine was hypothesized more than 50 years ago when F. Sicuteri demonstrated the occurrence of significantly elevated levels in urine of 5-hydroxyindoleacetic acid, stable metabolite of 5-HT, during migraine attacks.^[50] Since this, numerous studies have attempted to clarify the possible biochemical anomalies of 5-HT in migraine, mainly utilizing platelets as a model of serotonergic neurons. Studies from our laboratory have shown that the levels of platelet 5-HT fluctuate in female migraine sufferers differently from those in healthy woman in the different phases of the menses and, more importantly, the levels of the indole decrease significantly in the luteal phase in menstrual migraine before the painful attacks.^[51,52] The reason why the levels of 5-HT drop before the attack is not known. However, it is possible to conceive that there may occur a biochemical shift of tryptophan metabolism toward decarboxylation rather than hydroxylation, therein favoring an increase in the synthesis of tryptamine and a reduction in the synthesis 5-HT, respectively, in the synaptic clefts of neurons of the ANS nuclei of the brain stem.

GABA and Migraine

GABA is the main inhibitory neurotransmitter in the CNS. GABA plays an important role in the modulation of pain threshold. The antiepileptic drugs valproate and topiramate, the most efficacious drugs in preventing migraine without aura attacks, are potent GABAergic agonists.^[53] Other than this, however, direct evidence for a role of GABA-related abnormalities in migraine is very scarce. One study has shown that plasma levels of GABA are not detectable during migraine attacks, but after this phase, its plasma levels increase, suggesting that activation of the GABAergic pathways is necessary to end the pain crisis.^[54]

Mitochondrial Energy, Metabolic Shifts, and Migraine

An increasing number of studies suggest that migraine sufferers display a reduction in the metabolism of cellular energy in different tissues, including brain. The first line of evidence in support of this is the platelet anomalies. Platelets of migraineurs display elevated free intracytosolic calcium levels^[55] and abnormal high number of dense bodies together with increased levels of serotonin within these organelles.^[56] These abnormalities are accompanied by a reduction in dense body secretion when platelets are stimulated by collagen.^[57] The reason for the accumulation of dense bodies and the impaired secretion in response to agonists may be due to a decrease of multiple enzymatic activities found in the mitochondria of platelets of MWoA and migraine with aura (MWA) patients.^[58] The same mitochondrial energy defect(s) has (have) been demonstrated in brain and muscle in ^[31]pNMR spectroscopy studies in different types of headache patients.^[59]

The synthesis of neurotransmitters is energy dependent. A shift of tyrosine metabolism leading to increased levels of trace amines in migraine may depend on energy defects. This hypothesis is supported by a study of these amines in CSF of early postmortem subjects. In the first hours after death, the levels of tyr, Oct, and synephrine increase dramatically suggesting that when the brain energy fails, the activity of tyrosine decarboxylase prevails.^[60] Also, deposition of free radicals in brain stem structures of migraine patients may contribute to mitochondrial energy decline in these patients. The accumulation of iron ions is proportional to the frequency of attacks, being greatest in chronic migraine wherein the attacks may occur every day.^[61] It is known that deposition of iron ions deteriorate the surface of mitochondria and reduce the efficiency of the respiratory chain and the neuronal energy substrates. Thus, it is probable that the deposition of iron radicals may progressively favor tyrosine metabolism along the decarboxylation pathway and deteriorate the neurotransmission of the pain matrix.

Conclusion

All of the above results provide for a functional framework in which anomalies in different biochemical pathways together act in determining migraine. Although many steps remain speculative, future biochemical studies should be focused on the study of the functional role of the TAARs alone and together with other neuromodulators, in particular, those affecting serotoninergic (eg, tryptamine) and dopaminergic (phenylethylamine and phenylethanolamine) neurotransmission, in the CNS of patients with migraine and, possibly, in adequately stressed animal models. Also, eventual effects of elusive amines on ion channels present on sensory neurons, the activation of which are associated with allodynia and hyperalgesia, as well as their interaction with TAARs should be questioned. Some genes recently implicated in migraine (eg, TRPM8 and KCNK18) are, intriguingly, predominantly expressed in trigeminal and dorsal root ganglia, a finding suggestive of an important role in the initiation of the headache attack.^[62]

Another important point in need of clarification is the nature of the energy failure in migraine and the relationship between this failure and the metabolic alterations of the strategic amino acid parents of the dopaminergic and serotoninergic CNS circuitries. Studies on possible mutations or polymorphisms in genes that regulate the decarboxylase enzyme activity in brain are also warranted. These studies may shed light on the physiological and pathological significance of these ancient enzymes, of evolutionary importance, in humans. Oct and synephrine, in fact, are the main noradrenergic neurotransmitters found in the lowest species of the evolutionary scale, such as worms and insects.^[14] It is possible that in conditions of neuronal energy failure, as has been demonstrated in migraine, the metabolism regresses, under the push of an excitatory status of the cortex,^[3] into an archaic modality of neurotransmission, leading to modifications in the biochemical milieu of synaptic clefts of the pain matrix, the end result of which produces the migraine attacks.

Findings include the following:

• In five studies of chronic migraine (1508 patients; mean, 19.5 headaches monthly), botulinum toxin A significantly reduced the average number of headaches by 2.3 per month compared to placebo; the average monthly reduction in headaches was roughly 8 with botulinum and 6 with placebo.
• In seven studies of chronic tension headache (675 patients, mean, 25.2 headaches monthly), botulinum toxin A did not significantly reduce the average number of headaches compared to placebo.
• In nine studies of episodic migraine (1838 patients; mean, <15 headaches monthly), botulinum toxin A did not significantly reduce the average number of headaches compared to placebo.
• In the few studies that examined the proportion of patients experiencing 50% improvement in headache, botulinum was superior to placebo for chronic migraine; however, these trials included fewer than 100 patients.
• Adverse effects — especially ptosis, muscle weakness, and neck pain — were significantly more common with botulinum than with placebo.

Comment

For prophylaxis against chronic migraine, the average benefit for botulinum toxin A compared to placebo is statistically significant but clinically modest; the placebo effect is impressive in this study. Moreover, treatment is costly (up to several thousand dollars yearly), and side effects are frequent; hence, this intervention will not be worthwhile for most people.

April 24, 2012 (New Orleans, Louisiana) — New guidelines for the prevention of episodic migraine, co-developed by the American Academy of Neurology (AAN) and the American Headache Society (AHA), upgrade the level of evidence supporting the use of some drugs but downgrade others.

Major changes include a new Level A endorsement for topiramate, but gabapentin and verapamil and other calcium-channel blockers are now considered Level U, or without sufficient evidence for or against their usefulness.

“The guidelines tell us about the evidence,” Stephen D. Silberstein, MD, from the Jefferson Headache Center at Thomas Jefferson University in Philadelphia, Pennsylvania, lead author of the guidelines, told Medscape Medical News. “If there’s a drug out there that’s never been tested in migraine, that doesn’t mean it doesn’t work. The example is topiramate, which in the first guideline we didn’t have good evidence for.”

A second document looks separately at the role of nonsteroidal anti-inflammatory drugs (NSAIDs) and complementary treatments for migraine prevention. They did find sufficient evidence to allow recommendation of some of these treatments.

“Often patients will come to us who don’t want to take medications but love natural products,” Dr. Silberstein added. “Now we have, for the first time, a list of natural products that the patients can take, that the neurologists can recommend with proven efficacy.

“That to me is a major advantage,” he added. “If they’re going to take a natural product, at least take one that works.”

The guidelines were released here at the American Academy of Neurology’s 64th Annual Meeting and appear in the April 24 issue of Neurology.

Changing Criteria

The guidelines for migraine prevention were last updated in 2000. It’s estimated that approximately 38% of migraineurs would benefit from migraine prevention strategies, but only 3% to 13% receive it, the authors note. The document looks only at patients with episodic migraine, in which attacks occur less than 15 days per month, and does not deal with acute migraine treatment or prevention of chronic migraine. Similarly, the guidelines do not examine use of botulinum toxin in migraine; a new guideline is in development, but a previous 2008 guideline noted botulinum toxin is probably ineffective for migraine prevention (Level B).

The new revision was undertaken to include a number of new studies that have been published in the interim, Dr. Silberstein noted. In addition, “the Academy changed the criteria for class I studies, taking into account dropouts.”

It was on this basis that the level of evidence supporting gabapentin was changed in the current document, for example, because the quality of the trials was reclassified, he said. “The same thing happened for verapamil and the other calcium-channel blockers.”

The guidelines make the following recommendations on currently available drugs for migraine prevention:

Level A agents are established as effective and “should be offered for migraine prevention,” including:

• Antiepileptic drugs: divalproex sodium, sodium valproate, topiramate;
• Beta-blockers: metoprolol, propranolol, timolol; and
• Triptans: frovatriptan for short-term prevention of menstrual migraine.

Level B agents are “probably effective and should be considered for migraine prevention,” including:

• Antidepressants: amitriptyline, venlafaxine;
• Beta-blockers: atenolol, nadolol; and
• Triptans: naratriptan, zolmitriptan for short-term prevention of menstrual migraine.

Level C medications are “possibly effective and may be considered for migraine prevention,” including:

• Angiotensin-converting enzyme inhibitors: lisinopril;
• Angiotensin-receptor blockers: candesartan;
• Alpha-agonists: clonidine, guanfacine;
• Antiepileptic drugs: carbamazepine; and
• Beta-blockers: nebivolol, pindolol

Level U agents have evidence that is conflicting or inadequate to support or refute their use, including:

• Antiepileptic drugs: gabapentin;
• Antidepressants;
• Selective serotonin reuptake inhibitors (SSRIs)/selective serotonin-norepinephrine reuptake inhibitors (SNRIs): fluoxetine, fluvoxamine;
• Tricyclics: protriptyline;
• Antithrombotics: acenocoumarol, warfarin, picotamide;
• Beta-blockers: bisoprolol;
• Calcium-channel blockers: nicardipine, nifedipine, nimodipine, verapamil;
• Acetazolamide; and
• Cyclandelate.

Several other medications were found to be less than effective.

Level A negative: Lamotrigine was established as ineffective and shouldn’t be offered for migraine prevention.

Level B negative: Clomipramine was considered probably ineffective and shouldn’t be considered for migraine prevention.

Level C negative: The following medications were deemed “possibly ineffective” and may not be considered for migraine prevention:

• Acebutolol;
• Clonazepam;
• Nabumetone;
• Oxcarbazepine; and
• Telmisartan.

Dr. Silberstein emphasized, though, that just because a drug has a lower rating in terms of the level of evidence, that doesn’t mean it doesn’t work, only that the evidence is limited.

“So whenever we see these drugs that have been downgraded or uncertain, there’s always room for good clinical trials,” he said. Amitriptyline, for example, is widely used for migraine prevention, “but the old trials were not adequate,” he noted. “That doesn’t mean it doesn’t work. We often use it.”

Another group of agents that should be looked at more closely is the SNRIs, Dr. Silberstein added. Migraine is comorbid with depression, and depression is a risk factor for migraine, he noted. “It would be great if we could do studies of drugs that are used for depression to find out which work and don’t work for migraine.”

SSRIs, used to treat depression, are not effective for migraine, but more recent evidence suggests that the SNRIs, such as venlafaxine, may be effective for both migraine and depression. “So that to me is a low-hanging fruit that needs to be looked at,” he said.

However, the funding to study off-patent drugs for new indications is not always forthcoming, making these studies problematic.

“Here’s a point I would make,” Dr. Silberstein added. “Insurance carriers and agencies are always saying to us, ‘use generic or over-the-counter drugs first,’ and I would argue to them, ‘why don’t you support clinical trials of older generic drugs for modern indications, so we know whether or not they work, so we can use them?'”

NSAIDs and Complementary Approaches

In a separate document, the AAN/AHS guidelines committee reviewed evidence supporting the use of NSAIDs and other complementary therapies. Fifteen class I or class II studies involved these migraine prevention strategies.

Level A:

• Petasites or butterbur is effective and should be offered to patients to reduce the frequency and severity of attacks.

Level B agents considered probably effective:

• Fenoprofen;
• Ibuprofen;
• Ketoprofen;
• Naproxen;
• Naproxen sodium;
• MIG-99 (feverfew);
• Magnesium;
• Riboflavin (vitamin B2); and
• Subcutaneous histamine.

Level C medications considered possibly effective include:

• Cyproheptadine;
• Coenzyme Q10;
• Estrogen;
• Mefenamic acid; and
• Flurbiprofen.

Level U agents have evidence that is conflicting or inadequate to support or refute their use, including:

• Aspirin;
• Indomethacin;
• Omega-3; and
• Hyperbaric oxygen.

Level B negative: Montelukast was considered probably ineffective for migraine prevention.

Art and Science

Richard B. Lipton, MD, F. Lowe Professor and vice chair of neurology, professor of epidemiology and population health, professor of psychiatry and behavioral science, and director, Division of Cognitive Aging and Dementia and the Montefiore Headache Center at Albert Einstein College of Medicine in New York City, noted that the guidelines are useful to neurologists, particularly those who are not headache specialists, because migraine and other headache disorders are among the most common reason for patient visits.

The advantage of the new guidelines is that they summarize the state of evidence not only for agents that are approved by the Food and Drug Administration — of which there are only 4 — but for a broader range of therapies that have a strong evidence base, he noted.

Migraine is biologically heterogenous, and clinical trials focus on the average patient response, so the reality is that when it comes to an individual patient, there is still an art to it. “Guidelines are always better at summarizing the science than in teaching the art,” Dr. Lipton said.

He also applauded the examination of the complementary products. “To me, the crucial issue isn’t, is the product a natural product or a prescription drug? To me, the crucial question is, is the treatment safe and effective for the patient in front of me?”

Very solid evidence supports the use of petasites (butterbur), a natural product, for example, or riboflavin, a vitamin, that otherwise might be perceived as fringe therapies, “but they actually have a solid scientific foundation for efficacy, more solid than many prescription drugs that we use.” He cautioned, however, that butterbur is a complex natural extract, so buying a pure extract is important because the natural root has a toxic alkaloid in it. “If the extraction is not done correctly it can cause harm.”

He recommends the product from Weber & Weber, the company that has done the studies supporting its use, because of this concern, but added that he has no financial interest. “I just don’t want neurologists telling patients to take any butterbur they find.”

Dr. Silberstein reports he is on the advisory panel of and receives honoraria from AGA, Allergan, Amgen, Capnia, Coherex, Colucid, Cydex, GlaxoSmithKline, Lilly, MAP, Medtronic, Merck, Minster, Neuralieve, National Institute of Neurologic Disorders and Stroke (NINDS), Nu-Pathe, Pfizer, St. Jude Medical, and Valeant. He is on the speakers’ bureau of and receives honoraria from Endo Pharmaceuticals, GlaxoSmithKline, and Merck. He serves as a consultant for and receives honoraria from Amgen and Novartis. His employer receives research support from AGA, Allergan, Boston Scientific, Capnia, Coherex, Endo Pharmaceuticals, GlaxoSmithKline, Lilly, MAP, Medtronic, Merck, NINDS, NuPathe, St. Jude Medical, and Valeant Pharmaceuticals. Dr. Lipton has disclosed no relevant financial relationships.

American Academy of Neurology 64th Annual Meeting: Presented April 23, 2012.

Posted: 04/20/2012; Headache. 2012;52(3):409-421. © 2012 Blackwell Publishing
Abstract and Introduction
Abstract

Objective.— To provide evidence for the reliability and validity of the Migraine-Specific Quality of Life Questionnaire Version 2.1 (MSQ) for use in chronic migraine (CM) in adults.
Background.— MSQ is one of the most frequently utilized disease-specific tools assessing impact of migraine on health-related quality of life (HRQL). However, evidence for its reliability and validity are based on studies in episodic migraine (EM) populations. Additional studies assessing the reliability and validity of the MSQ in patients with CM are needed.
Methods.— Cross-sectional data were collected via web-based survey in 9 countries/regions. Participants were classified as having CM (≥15 headache days/month)

Results.— A total of 8726 eligible respondents were classified: 5.7% CM (n = 499) and 94.3% EM (n = 8227). Subjects were mostly female (83.5%) with a mean (±SD) age of 40.3 ± 11.4, and were similar between the 2 groups. MSQ domain scores for CM and EM groups, respectively, were: RP = 61.4 ± 26.1 and 71.7 ± 24.0; RR = 44.4 ± 22.1 and 56.5 ± 24.1; EF = 48.3 ± 28.1 and 67.2 ± 26.7. Internal consistency of the overall sample for RP, RR, and EF was 0.90, 0.96, and 0.87, respectively. Similar values were observed for CM and EM. MSQ scores for the overall sample correlated moderately to highly with scores from the PHQ-4 (r = −0.21 to −0.42), MIDAS (r = −0.38 to −0.39), and HIT-6 (r = −0.60 to −0.71). Similar values were observed for CM and EM. Known-groups validity indicated significant differences (P < .0001) in the hypothesized direction between CM and EM for RP (F = 86.19), RR (F = 119.24), and EF (F = 235.90).
Conclusion.— The MSQ is a reliable and valid questionnaire in the CM population that can differentiate the functional impact between CM and EM. The MSQ can assist researchers in evaluating treatment effectiveness by obtaining input directly from the patients on multidimensional aspects other than frequency of headache days.

Introduction

Migraine adversely affects an estimated 12% of the US population.^[1–3] Although the clinical course of migraine across a patient’s life span is not yet fully understood, there is increasing evidence that, for some patients, the frequency of headache attacks increases over time.^[4]

Chronic migraine (CM) is currently defined as a complication of migraine characterized by ≥15 headache days per month (HDPM) for at least 3 months, occurring in patients with at least 5 attacks fulfilling criteria for migraine without aura and for whom headache fulfilled criteria for pain and associated symptoms of migraine without aura at least 8 HDPM in the past 3 months.^[5] In addition, the International Classification of Headache Disorders, Revised Second Edition (ICHD-IIR) diagnostic criteria exclude those patients with a diagnosis of medication overuse.^[5] Population-based studies suggest that 1.4–2.2% of the general population suffer from CM.^[6–8] It is estimated that migraine patients transit from episodic migraine (EM) to CM at a rate of 2.5% of patients per year.^[4] Studies have suggested that a higher frequency of headache attacks is associated with significantly greater levels of functional disability and reduced health-related quality of life (HRQL).^[9,10]

Chronic migraine patients have been found to have reduced productivity and more missed days of work, school, housework, or family and leisure activities when compared to patients with EM^[9] and are estimated to incur total costs (both direct and indirect) that are 4 times greater than those for EM patients.^[11] Despite the clinical and economic burden of CM compared to EM, CM is frequently undertreated and underdiagnosed.^[12–14]

Researchers and clinical practitioners alike have become increasingly aware that the impact of migraine cannot be fully assessed through measures that focus exclusively on pain and frequency of headaches. Patient-reported outcome (PRO) instruments are recognized as important tools in assessing the impact of a given disease state on HRQL in clinical practice.^[15]

Both generic and disease-specific PRO measures can be used to evaluate HRQL in migraine patients. Although generic PRO measures allow for a direct comparison of disease burden across different conditions, disease-specific PROs offer a more precise level of measurement, given their focus on limitations or problems that are associated with a particular disease. For this reason, changes in HRQL due to treatment are often better captured by disease-specific PROs. Accordingly, experts have recommended^[16–18] the use of disease-specific PRO measures to quantify the potential benefits of treatment in migraine clinical trials. Previous literature has summarized characteristics of both generic and disease-specific quality of life measures commonly used in headache patients, and these measures were found to vary in their specificity, the dimensions they assess, the time frame they address, as well as their psychometric properties.^[15] Accordingly, as most disease-specific PROs are designed to measure impact on HRQL that is directly attributable to the disease of interest, the reliability of the results obtained with these instruments still requires careful evaluation of their psychometric properties and overall validity among the clinical population of interest.

The Migraine-Specific Quality of Life Questionnaire Version 2.1 (MSQ) is one of the most frequently utilized disease-specific tools assessing the impact of migraine on HRQL.^[19–23] The MSQ measures the impact of migraine on the patient’s HRQL over the past 4 weeks across 3 dimensions: Role Function-Restrictive (RR), Role Function-Preventive (RP), and Emotional Function (EF). The MSQ was developed from an expert-based item review of the migraine literature and validated in a clinical sample of 458 new and stable EM patients.^[21] In the validation study, the MSQ revealed high internal consistency (Cronbach’s α = 0.79 to 0.85), a moderate to strong convergent validity, as well as an adequate discriminant validity. Martin and Colleagues^[22] performed a multicenter study that further supported the evidence of a high internal consistency (Cronbach’s α = 0.86 to 0.96), strong reliability, and good validity of the 14-item MSQ among 267 participants.

Although there is evidence for reliability and validity of the MSQ, these studies were conducted in EM populations.^[21,22,24] Given the extensive use of the MSQ in migraine research, its integral role within clinical practice, and the emerging evidence regarding the need for practitioners to distinguish CM from EM, additional studies assessing the reliability and validity of the MSQ in patients with CM are needed. The current study aims to provide evidence on the reliability and validity of the MSQ in CM patients and to evaluate its ability to capture differences in HRQL between CM and EM patients.

Methods

Subjects

The International Burden of Migraine Study (IBMS) was a web-based cross-sectional observational study that collected survey data on migraine patients from 9 countries/regions (the USA, Canada, France, Germany, Spain, the UK, Australia, Italy, and Taiwan) between February and April of 2009.^[25] Participants were recruited from a population of panelists, maintained by Synovate Healthcare, who had already reported suffering from headaches and/or migraines. Participants provided consent by “opting-in” using a web link (provided in the email invitation) as a proxy for written informed consent. To be considered for participation in the study, respondents had to meet the following criteria: (1) be 18 years of age or older; (2) have an active email address; (3) report having experienced headaches during the last 3 months not associated with a cold, the flu, a head injury, or a hangover; (4) provide conformed consent by “opting-in” via a web link in the email invitation; (5) have migraine symptoms.

Eligibility and migraine diagnostic features were assessed using validated screening questions^[14] and ICHD-IIR migraine diagnostic criteria.^[26] Eligible participants were further categorized as EM (<15 HDPM) or CM (≥15 headaches days month). A flow diagram of study participants and eligibility is presented in the Figure. A total of 63,001 panelists in 9 countries were contacted. Of those, 30.7% (n = 19,365) responded to the email invitation and completed the eligibility screening and 55.0% (n = 10,650) were eligible to complete the survey based on screening criteria. Surveys were completed by 81.9% (n = 8,726) of eligible responders. Detailed description of study design and methods has been previously published.^[25]

The authors had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Measures

For the respondents who met the screening criteria based on number of headache days in the previous 3 months, the remainder of the survey questions assessed migraine severity, participant socio-demographic and clinical characteristics, healthcare resource utilization, productivity, and HRQL.

Socio-Demographic and Clinical Characteristics Participants reported their age, gender, race, marital status, employment status, education, income, height, and weight. Participants were asked to provide the frequency of the following headache symptoms: severity of pain, throbbing, getting worse with activity, worse on 1 side, nausea, photosensitivity, and phonosensitivity. The survey also included specific questions regarding the typical duration of headaches with and without medication. The presence of comorbidities (pain, vascular disease, vascular events, psychiatric conditions, or other) was also collected as part of the survey. As part of screening, participants were asked to report the number of days in the last 3 months that they had a headache of any intensity.

Migraine-Specific Quality of Life Questionnaire Version 2.1 The 14-item MSQ is designed to measure how migraines affect and/or limit daily functioning across 3 domains: RR (7 items assessing how migraines limit one’s daily social and work-related activities), RP (4 items assessing how migraines prevent these activities), and EF (3 items assessing the emotions associated with migraines). Participants respond to items using a 6-point scale, “none of the time,””a little bit of the time,””some of the time,””a good bit of the time,””most of the time,” and “all of the time,” which are assigned scores of 1 to 6, respectively. Raw dimension scores are computed as a sum of item responses and are rescaled to a 0–100 scale, where higher scores indicate better HRQL.

Multiple studies have demonstrated good reliability and validity of the MSQ in subjects with EM.^{[21,22,24,27]} The MSQ has been administered in several efficacy trials of EM and CM treatment and has shown to be responsive to treatment.^[19,28,29] Results from a study of 119 migraine patients recruited at 4 headache clinics revealed that the effect sizes of the MSQ were moderate to large at 4 and 12 weeks.^[30] More recently, inter- and intra-individual minimally important differences (MID) have been established^[31] using data from 2 randomized clinical trials of migraine prevention therapy and from 1 cross-sectional survey of headache patients.

Headache Impact Test (HIT-6) The HIT-6 assesses the impact of headache on participants’ lives in the past 4 weeks. Six domains are represented by the HIT-6: pain, role functioning, social functioning, energy or fatigue, cognition, and emotional distress.^[32] Responses are provided on a 5-point scale in the categories “never,””rarely,””sometimes,””very often,” and “always,” and are assigned values of 6, 8, 10, 11, and 13, respectively. The HIT-6 total score is obtained from simple summation of the 6 items and ranges between 36 and 78, with larger scores reflecting greater impact. Four groups have been derived to aid in the interpretation of HIT-6 scores: scores ≤49 represent little or no impact, scores between 50 and 55 represent some impact, scores between 56 and 59 represent substantial impact, and score ≥60 indicate severe impact.^[33] The instrument has shown good reliability, construct, and convergent and face validity,^[32,34] and its MID has been evaluated in a sample of patients with chronic daily headache.^[35]

Migraine Disability Assessment Scale (MIDAS) The MIDAS was developed to measure headache-related disability in 3 domains: school/work; household work; and family, social, or leisure activities.^[36] The disability is quantified by the total number of days of activity limitations due to migraine in the past 3 months. Two additional questions assess the frequency and intensity of a headache. A total score is calculated by adding the 5 headache-related disability items, with higher scores indicating increased disability due to headache. The MIDAS has an acceptable internal consistency, and a moderate 3-month test–retest reliability.^[36] MIDAS scores had moderate correlations with equivalent measures derived from 90-day diary data.^[36] Based on physicians’ judgment of MIDAS scores on varying levels of migraine patient’s activity limitation and treatment needs, 4 grades of headache-related disability have been derived from the total MIDAS score: grade I for “minimal or infrequent disability” (0–5), grade II for “mild or infrequent disability” (6–10), grade III for “moderate disability” (11–20), and grade IV for “severe disability” (≥21).^[36] Although this scoring system works well for EM, a previous study found that further subdivision of grade IV allows for a clear examination of variation within CM patients.^[25] Accordingly, for this study, grade IV was subdivided into grade IV-A, severe disability (scores of 21–40), and grade IV-B, very severe (scores of 41–270).

Patient Health Questionnaire (PHQ-4) The PHQ-4 constitutes a brief screening measure for depression and anxiety symptoms in the past 2 weeks. The PHQ-4 scale consists of the 2 core DSM-IV items for major depressive disorder and generalized anxiety disorder, respectively.^[37–39] Each of the 4 items is answered on a 4-point scale: “not at all” (0), “several days” (1), “more than half the days” (2), and “nearly every day” (3). Total scores range from 0 to 12, with a higher score indicating a greater likelihood of an underlying depressive or anxiety disorder. Scores are rated as normal (0–2), mild (3–5), moderate (6–8), and severe (9–12). Two discrete factors of depression and anxiety were found to explain 84% of the total variance in the PHQ-4 and higher scores were strongly associated with functional impairment, disability days, and healthcare use.^[40] Major depressive disorder scores ≥3 have demonstrated sensitivity of 83% and specificity of 90%,^[41] while similar scores on the generalized anxiety disorder items demonstrated good sensitivity (86%) and good specificity (83%) for identifying patients with depression.^[42] Recent studies have confirmed the reliability and validity of the PHQ-4 as a measure of depression and anxiety using a representative sample of the German general population.^[43]

Statistical Analysis

Reliability Analyses Internal consistency reliability was assessed by calculating Cronbach’s α across the 3 MSQ domains, for the whole sample and separately for CM and EM patients. Reliability was determined using the conventional threshold for Cronbach’s α of 0.70.^[44]

Convergent and Discriminant Validity Convergent and discriminant validity was assessed by evaluating the Pearson correlation coefficients of the MSQ scores and HDPM, as well as scores on the following HRQL instruments: HIT-6, MIDAS, and PHQ-4. Given that the HIT-6 and the MIDAS are disease-specific instruments and assess the impact of migraine on HRQL, it was hypothesized that correlations between the MSQ and the HIT-6 and the MSQ and the MIDAS would be higher than those between the MSQ and the PHQ-4. Compared to the MSQ RR and RP scales, it was also hypothesized that the MSQ EF scale would more highly correlate with the PHQ-4. Moderate correlations between HDPM and MSQ scores were expected.

Known-Groups Validity Construct validity of the MSQ was further evaluated using the method of known-groups validity.^[45] Known-groups validity was assessed using analysis of variance (ANOVA) methods to compare mean MSQ score differences across the following criterion measures: (1) patients who differed in headache frequency (CM and EM patients); (2) patients who differed in migraine impact severity, as indicated by the HIT-6 score (little or no impact, some impact, substantial impact, and severe impact); (3) patients who differed in migraine impact severity according to MIDAS grade (I [0–6], II [7–10], III [11–20], and IV [≥21]); (4) patients who differed in risk for depression and anxiety, as indicated by the PHQ-4 score (normal, mild, moderate, and severe). We expected that lower mean MSQ scores would be observed in patients with CM than those with EM. In addition, it was hypothesized that MSQ scores would be monotonically lower across greater impact severity levels and greater levels of depression and anxiety risk.

Results

Subject Characteristics

A total of 8,726 eligible respondents were classified as follows: 5.7% CM (n = 499), 94.3% EM (n = 8,227) (Table 1). Migraine patients were mostly female (83.5%), white/Caucasian (86.1%), with a mean (±SD) age of 40.3 (±11.4) years. Approximately one-quarter of the total sample (24.4%) had completed high school and a similar proportion (25.2%) had some college or had an associate degree. Two-thirds of the total sample (66.4%) had been told by a healthcare provider that they suffered from migraines and the majority (78.9%) reported experiencing severe headache pain. Socio-demographic characteristics were mostly similar across the CM and EM groups, with the exception of the distribution of Asian and Hispanic participants. The proportion of Asians in the CM group was lower (1.8% vs 8.3% in the EM group), while the proportion of Hispanics was higher (5.0% vs 2.5% in the EM group). In addition, a greater proportion of CM patients reported severe headache pain (92.4% vs 78.1% in the EM group).

Table 1. Subject Characteristics

Characteristic	Chronic Migraine (N = 499)	Episodic Migraine (N = 8227)	Total (N = 8726)
Age, mean (SD)	41.7 (12.1)	40.2 (11.4)	40.3 (11.4)
Female, n (%)	427 (85.6)	6862 (83.4)	7289 (83.5)
Race/ethnicity, n (%)
White/Caucasian	446 (89.4)	7064 (85.9)	7510 (86.1)
Asian	9 (1.8)	684 (8.3)	693 (7.9)
Hispanic or Latino/Latin American	25 (5.0)	214 (2.6)	239 (2.7)
Other	9 (1.8)	164 (2.0)	173 (2.0)
Black	5 (1.0)	60 (0.7)	65 (0.7)
Prefer not to answer	5 (1.0)	41 (0.5)	46 (0.5)
Education, n (%)
Less than a high school diploma	70 (14.0)	1128 (13.7)	1198 (13.7)
High school graduate	123 (24.6)	2004 (24.4)	2127 (24.4)
Some college, no degree/Associate degree	152 (30.5)	2051 (24.9)	2203 (25.2)
Bachelor’s degree	63 (12.6)	1418 (17.2)	1481 (17.0)
Master’s degree	28 (5.6)	502 (6.1)	530 (6.1)
Doctoral degree	8 (1.6)	111 (1.3)	119 (1.4)
Professional degree	33 (6.6)	747 (9.1)	780 (8.9)
Other	16 (3.2)	202 (2.5)	218 (2.5)
Prefer not to answer	6 (1.2)	64 (0.8)	70 (0.8)
Headache pain severity, n (%)
Mild	2 (0.4)	114 (1.4)	116 (1.3)
Moderate	36 (7.2)	1690 (20.5)	726 (19.8)
Severe	461 (92.4)	6423 (78.1)	6884 (78.9)
Comorbidities, n (%)
Pain	208 (41.7)	2739 (33.3)	2947 (33.8)
Psychiatric disorders	231 (46.3)	2347 (28.5)	2578 (29.5)
Vascular disease events	41 (8.2)	275 (3.3)	316 (3.6)
Vascular disease risk factors	208 (41.7)	2739 (33.3)	2947 (33.8)
Other conditions	249 (49.9)	3089 (37.5)	3338 (38.3)

The MSQ Item Distributional Characteristics

Mean scores for MSQ items on the RR scale (items 1–7) were similar, ranging from 3.0 to 3.4 ( Table 2 ). Mean scores for MSQ items on the RP scale (items 8–11) were lower than those of the items making up the RR scale and ranged from 2.3 to 2.7. Unlike the RR and RP scales, a greater variation in mean scores was observed across the EF scale items (items 12–14) with mean scores of 2.4 in the 2 items concerning “feeling like a burden on others” (item 13) and “being afraid of letting others down” (item 14) and a mean score of 3.3 for the item concerning “feeling fed up or frustrated” (item 12) because of migraines. No ceiling effects were observed among the 14 items (range: 4–12%). However, floor effects were seen for 2 EF scale items (“being a burden on others” and “being afraid of letting others down”) and 3 RP scale items (“canceling work or daily activities,””help with handling routine tasks,” and “being unable to attend social activities”), with over 30% of EM patients obtaining the lowest score in these items.

Table 2. The MSQ Item Distributional Characteristics

In the Past 4 Weeks How Often …	Mean	Standard Deviation	% Floor	% Ceiling
Role Function-Restrictive
[…] have migraines interfered with how well you dealt with family, friends and others who are close to you?	3.01	1.27	11.3	4.4
[…] have migraines interfered with your leisure time activities, such as reading or exercising?	3.31	1.36	8.8	8.4
[…] have you had difficulty in performing work or daily activities because of migraine symptoms?	3.12	1.30	10.1	5.5
[…] did migraines keep you from getting as much done at work or at home?	3.21	1.36	10.0	7.1
[…] did migraines limit your ability to concentrate on work or daily activities?	3.27	1.32	8.4	7.3
[…] have migraines left you too tired to do work or daily activities?	3.17	1.38	11.8	6.4
[…] have migraines limited the number of days you have felt energetic?	3.40	1.37	8.2	8.7
Role Function-Preventive
[…] have you had to cancel work or daily activities because you had a migraine?	2.41	1.37	32.7	3.7
[…] did you need help in handling routine tasks such as every day household chores, doing necessary business, shopping, or caring for others, when you had a migraine?	2.28	1.37	38.0	3.5
[…] did you have to stop work or daily activities to deal with migraine symptoms?	2.67	1.39	23.0	4.8
[…] were you not able to go to social activities such as parties, dinner with friends, because you had a migraine?	2.42	1.40	32.4	5.0
Emotional Function
[…] have you felt fed up or frustrated because of your migraines?	3.29	1.55	14.1	12.0
[…] have you felt like you were a burden on others because of your migraines?	2.37	1.50	40.4	5.5
[…] have you been afraid of letting others down because of your migraines?	2.42	1.51	38.7	5.5

MSQ = Migraine-Specific Quality of Life Questionnaire Version 2.1.

Reliability and Validity Analyses

Results of the reliability analyses of the MSQ among migraine sufferers are presented in Table 3 . Cronbach’s α indicated excellent^[44] internal consistency reliability for the entire sample (range 0.87 to 0.96) and across migraine frequency groups (CM range: 0.85–0.95; EM range: 0.86–0.96).

The MSQ scales were moderately to highly correlated with the HIT-6 (r = −0.60 to −0.71), MIDAS (r = −0.38 to −0.57), and PHQ-4 (r = −0.30 to −0.47), but had low correlation with HDPM (r = −0.24 to −0.14; Table 4 ). All correlations were statistically significant (P < .01). The higher correlations observed between all scales of the MSQ and the HIT-6 and the MIDAS, as well as the MSQ EF scale and the PHQ-4, supported convergent validity of the MSQ, and the lower correlations observed between the MSQ RR and RP scales and the PHQ-4 supported discriminant validity of the MSQ. Furthermore, correlations of the HIT-6 and the MIDAS with the MSQ tended to be highest for the RR scale, closely followed by the RP and EF scales. Conversely, correlations of the PHQ-4 and HDPM with the MSQ were highest for the EF scale, followed by the RR and RP scales. Although slightly lower correlation values were observed among the EM group when compared to CM, the magnitude of correlations tended to be similar across the 2 groups.

Table 5 presents the means and standard deviations of MSQ scores across several criterion measures that are known to represent different levels of migraine impact. The results indicated that the mean MSQ scale scores decreased with increasing headache severity levels, for all 4 criterion measures. For CM and EM groups, mean (±SD) MSQ were RR = 44.4 (±22.1) and 56.5 (±24.1), RP = 61.4 (±26.1) and 71.7 (±24.1), EF = 48.3 (±28.1) and 67.2 (±26.6), respectively. The differences between CM and EM exceeded the recommended MID values of 3.2, 4.6, and 7.5 for RR, RP, and EF, respectively.^[31] Although all 3 MSQ scales resulted in mean scores that were significantly different across migraine frequency groups, the EF scale appeared to best capture the differences between CM and EM patients, as indicated by a larger F-statistic. In discriminating across migraine impact levels (for both HIT-6 impact groups and MIDAS grades) the RR scale performed the best, whereas the EF scale performed the best in discriminating across groups that differed in risk of anxiety/depression. Overall, these results indicate that the MSQ can adequately differentiate the impact that migraine has on HRQL, overall and across groups varying in headache frequency.

Table 5. Known-Groups Validity: Mean (SD) MSQ Scales by Several Criterion Measures

Migraine Frequency
	Chronic Migraine (N = 499)	Episodic Migraine (N = 8,227)				F
RR	44.37 (22.07)	56.46 (24.13)				119.24‡
RP	61.37 (26.10)	71.68 (23.96)				86.19‡
EF	48.27 (28.12)	67.20 (26.64)				235.90‡
Migraine Impact (HIT-6)
	Little or No Impact (N = 202)	Some Impact (N = 617)	Substantial Impact (N = 989)	Severe Impact (N = 6,251)		F
RR	90.27 (12.60)	81.30 (14.89)	73.83 (15.16)	47.88 (22.16)		1,042.28‡
RP	95.30 (11.54)	91.23 (12.12)	87.13 (13.59)	64.82 (24.34)		580.04‡
EF	94.19 (13.09)	90.46 (13.05)	84.56 (16.12)	58.83 (26.94)		646.70‡
Migraine Impact (MIDAS)
	Grade I (N = 2,412)	Grade II (N = 1,560)	Grade III (N = 1,939)	Grade IV-A (N = 1,838)	Grade V-B (N = 977)	F
RR	72.96 (19.81)	59.55 (21.11)	51.92 (21.32)	44.62 (21.06)	35.94 (19.86)	805.41‡
RP	85.76 (17.99)	76.33 (20.37)	68.61 (22.18)	60.23 (23.31)	51.88 (24.41)	633.78‡
EF	81.92 (19.73)	72.58 (23.13)	63.65 (25.44)	54.87 (26.01)	42.83 (26.62)	633.72‡
Risk of Anxiety/Depression (PHQ-4)
	Normal (N = 3,478)	Mild (N = 2,930)	Moderate (N = 1,670)	Severe (N = 648)		F
RR	62.83 (24.15)	55.88 (21.80)	46.85 (22.26)	40.38 (24.73)		287.84‡
RP	78.24 (22.11)	71.07 (22.06)	62.11 (24.75)	56.00 (27.89)		287.42‡
EF	76.94 (23.28)	66.10 (23.99)	52.72 (26.43)	42.61 (30.46)		580.26‡

‡P < .0001.
EF = Emotional Function; HIT-6 = Headache Impact Test-6; MIDAS = Migraine Disability Assessment Questionnaire; MSQ = Migraine-Specific Quality of Life Questionnaire Version 2.1; PHQ-4 = Patient Health Questionnaire-4; RP = Role-Preventative; RR = Role-Restrictive; SD = standard deviation.

Discussion

The current study demonstrates that the MSQ is a reliable and valid measure of the HRQL among adults with CM and can differentiate the impact of headache across the spectrum of headache frequency as defined for EM and CM. Floor effects were observed for the same 5 items among both CM and EM, while ceiling effects were only observed for 1 item among the CM group. Study results also indicated that the MSQ has high internal consistency and reliability among migraine sufferers, with our results being comparable to those of previous validation studies.^[21,22] Consistent with pre-hypothesized relationships between the MSQ scales and other HRQL instruments, convergent and discriminant validity were supported by relatively higher correlations between the MSQ and the HIT-6 and the MIDAS and lower correlations between the MSQ and the PHQ-4. Construct validity was further confirmed within the framework of known-groups validity, with results showing that MSQ scores differed significantly across CM and EM patients and other important headache severity criterion measures.

Unexpectedly, the MSQ scales had low correlations with HDPM. The low correlations may be at least partially explained by the fact that the MSQ is designed to capture the multifaceted construct of migraine impact, which includes not only the frequency but also the intensity and the duration of headaches and the patient’s own evaluation of how migraines impact their quality of life. Indeed, other studies^[46,47] have reported disability to be more strongly associated with headache pain severity rather than with headache frequency, which further concurs with our findings. In the MSQ development and validation study,^[21] frequency of headaches over the past 12 months had low to moderate correlations with the MSQ scales. In that study, from among the 3 MSQ scales, the EF scale was the most strongly correlated (r = −0.48) with headache frequency, followed by the RR (r = −0.27) and lastly the RP (r = −0.14), a ranking of correlations that was mirrored in our results (for CM and EM combined only).

One limitation of the study was that the migraine diagnosis was not based on physician report but used the participants’ self-report to the migraine screening questions.^[25] Therefore, it is possible that some respondents were misclassified. Furthermore, electronic data collection conducted in this study design may have introduced participation bias because individuals lacking appropriate computer skills, access, or willingness may not have been included.^[25] Finally, given the cross-sectional study design, certain psychometric properties, such as test–retest reliability and responsiveness, could not be assessed.

Despite these limitations, the results of this study provide important new evidence for the psychometric reliability and validity of the MSQ. Although the MSQ has been shown to be a valid tool for measuring functional status and the effect of treatment among general migraine patients,^[20–22,24] the present study expands the scope of these findings by providing quantitative indicators of the validity of the MSQ specifically among CM adults, a group that has traditionally been understudied in validation analyses of headache- or migraine-specific HRQL measures.

The MSQ has been successfully used to assess the effect of therapy in several randomized clinical trials of migraine treatment,^[19,29] including clinical trials among patients with CM.^[28,48,49] HRQL instruments are most effective when they can capture clinically meaningful data while minimizing respondent burden without compromising validity.^[50] Accordingly, the combination of these key elements makes the MSQ a valuable tool, not only for use in clinical trials, but also for clinicians who manage treatment of CM and EM patients.

The importance of differentiating between headache subtypes in order to optimize treatment is an increasingly relevant issue for clinical practitioners. PRO instruments can be integrated within clinical practice to guide diagnosis and treatment^[15] that is targeted to the correct subtype of migraine. The growing interest^[51] in using HRQL measures to characterize differences between EM and CM patients supports the need to study the psychometric properties of these tools. Although several studies have examined the validity of the MSQ using samples of EM patients or general migraine patients, this was the first study that examined the validity of the MSQ in capturing distinct domains of migraine impact, across patients with different headache frequency levels.

Longitudinal studies exploring test–retest and responsiveness are recommended in the future to assess the reliability and validity of the MSQ in CM patients. In addition, continued examination of the psychometric properties of HRQL instruments that characterize the impact of migraine in CM and EM patients is needed to expand the current understanding of differences across these 2 groups.

Conclusions

The MSQ has been shown to be a reliable and valid measure of HRQL among adults with CM and can differentiate the functional impact of headache across the spectrum of headache frequency as defined for EM and CM. The MSQ can assist researchers in evaluating treatment effectiveness by obtaining input directly from the patients on multidimensional aspects other than frequency of headache days.

Sidebar

Statement of Authorship

Category 1

(a) Conception and Design
Christine L. Bagley; Sepideh F. Varon; Gregory A. Maglinte

(b) Acquisition of Data
Christine L. Bagley; Sepideh F. Varon; Gregory A. Maglinte; Regina Rendas-Baum; Min Yang

(c) Analysis and Interpretation of Data
Christine L. Bagley; Gregory A. Maglinte; Regina Rendas-Baum; Min Yang; Sepideh F. Varon

Category 2

(a) Drafting the Article
Christine L. Bagley; Regina Rendas-Baum; Min Yang; Gregory A. Maglinte; Sepideh F. Varon; Jeff Lee; Mark Kosinski

(b) Revising It for Intellectual Content
Christine L. Bagley; Regina Rendas-Baum; Min Yang; Gregory A. Maglinte; Sepideh F. Varon; Jeff Lee; Mark Kosinski

Category 3

(a) Final Approval of the Completed Article
Christine L. Bagley; Regina Rendas-Baum; Min Yang; Gregory A. Maglinte; Sepideh F. Varon; Jeff Lee; Mark Kosinski

Migraine is a chronic neurologic disorder with heterogeneous characteristics resulting in a range of symptom profiles, burden, and disability. Migraine affects nearly 12% of the adult population in occidental countries, imposing considerable economic and social losses. The pharmacologic treatment of migraine includes preventive and acute strategies. A better understanding of the migraine pathophysiology along with the discovery of novel molecular targets has lead to a growing number of upcoming therapeutic proposals. This review focuses on new and emerging agents for the treatment of migraine.

Background

Migraine is a highly prevalent, disabling, undiagnosed, and undertreated disease.[1] The phenomenon is a primary neurologic disorder with a clear genetic basis.[2,3] For some uncommon forms of migraine, such as familial hemiplegic migraine, specific pathogenic genes have been identified. The most common mutation affects a gene on chromosome 19 that encodes for a neuronal calcium channel.[4] This observation suggests that other forms of migraine may also be ion channelopathies. During the migraine attack, neural events result in the dilatation of meningeal blood vessels that, in turn, causes pain, further nerve activation, and inflammation.[5] Because neural events are linked to vascular events, migraine is considered a neurovascular headache disorder.

Migraine probably results from dysfunction of brainstem areas involved in the modulation of craniovascular afferent fibers.[2-5] Brainstem activation may also lead to activation of ascending and descending pathways, with initiation of a perimeningeal vasodilatation and neurogenic inflammation. The pain is understood as a combination of altered perception (related to peripheral or central sensitization) of stimuli that are usually not painful, and the activation of a feed-forward neurovascular dilator mechanism in the first (ophthalmic) division of the trigeminal nerve. Cortical spreading depression is the presumed substrate of migraine aura; spreading depression also occurs in migraine without aura.

The past 15 years has witnessed the development of an arsenal of drugs that act on excitatory glutamate-mediated activity or inhibitory gamma-aminobutyric acid (GABA)-mediated activity, actions that theoretically provide cortical stabilization, therefore counteracting the imbalance supposedly existent in the migraineur’s brain.[4,5] In addition, the progressive knowledge about the sequence of phenomena occurring during a migraine attack has stimulated interest in agents that may block the cortical spreading depression, a presumed substrate of migraine. Other targets include the blockage of proinflammatory substances released at the level of the trigeminal end, including neuropeptides involved in initiating the pain of migraine, and substances that may block the sensitization of peripheral and central trigeminal nociceptive pathways.[1,2, 5-9]

In this review, we discuss new and emerging agents for the treatment of migraine. For both preventive and acute therapies, we first discuss medications that have been recently proposed for migraine, and then medications in development. None of the drugs discussed, with the exception of topiramate (TPM), have received an indication for the treatment of migraine, according to regulatory agencies.
Need for New Treatments for Migraine

As soon as a clinical diagnosis of migraine is made and disability and comorbidities have been assessed, the next task is to develop an individualized treatment plan. This plan usually has a number of goals that vary in priority with the patient’s headache characteristics and treatment preferences. The plan usually includes educating patients about their illness and its management (eg, mechanisms, recognizing and avoiding triggers, and lifestyle changes), acute treatment, and preventive treatment.

The objective of acute migraine therapy is to restore the patient’s ability to function by rapidly and consistently alleviating the head pain and the associated symptoms.[8,10] The objective of prevention is to reduce the frequency and impacts of attacks.

Despite the tremendous advances in the pharmacologic management of migraine, available options are still far from the optimum. Nearly 31% of the patients taking a triptan for acute migraine treatment discontinue its use because of lack of efficacy, headache recurrence, cost, and/or side effects.[11] In most trials, the therapeutic gain (efficacy of the drug subtracted by the efficacy of placebo) for the triptans is roughly 25% to 35% at 2 hours after treatment, and the absolute response usually does not exceed 70%.[12] In most trials of migraine prophylaxis, only 50% of the subjects experience more than 50% reduction of their headache frequency after 3 months of treatment.[8,10] Therefore, despite the advances in the past decade, new medicines for the management of migraine are needed.
Brief Review of Existing Treatments

Pharmacologic treatment of migraine is divided into acute and prophylactic modalities. Acute treatment can be subdivided into nonspecific agents (such as aspirin, acetaminophen, nonsteroidal anti-inflammatory drugs, opiates, and combination analgesics) and migraine-specific treatments (ergotamine, dihydroergotamine, and the triptans). The US Headache Consortium Guidelines recommend stratified care that is based on the level of disability to help physicians target patients who require careful assessment and treatment.[13] Thus, substantial clinical evidence exists for using disability to guide the assessment and treatment strategy (Figure 1). For migraine sufferers with attack-related disability and no contraindications, triptans ( Table 1 ) should be the class of choice.[14]

According to the US Headache Consortium Guidelines, preventive treatment should be considered when (1) the migraine significantly interferes with the patient’s daily routine despite acute treatment (eg, 2 or more attacks a month that produce disability that lasts ≥ 3 days or headache attacks that are infrequent but produce profound disability); (2) failure, contraindication to, or troublesome side effects occur from acute medications; (3) patients overuse acute medications; or (4) very frequent headaches (more than 2 a week) occur, or the pattern of attacks increases over time, with the risk of developing rebound headache from the repeated use of medicines taken for the acute attack.[9] Selected current preventive medications are displayed in Table 2 .
Recent Advances in Migraine Prophylaxis

In this section we highlight drugs that recently received approval for migraine treatment (TPM) or are available and sometimes used off-label. All drugs discussed in this section are for the preventive treatment of migraine.
TPM

TPM was recently approved by the US Food and Drug Administration (FDA) for migraine prophylaxis. It is a neuromodulator with a structurally unique formula that provides multiple mechanisms of action and can influence the activity of some types of voltage-activated Na+ and Ca++ channels, the GABAA receptor, and the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)/kainate subtype of glutamate receptors. TPM also has inhibition properties on specific carbonic anhydrase (CA) II and CA IV isozymes of CA.[15,16] TPM exerts its effects on voltage-activated Na+ and Ca++ channels, GABAA receptors, and AMPA/kainate receptors through protein phosphorylation. Because some of its effects are influenced by the phosphorylation state of these receptors, it has been postulated that TPM may bind to the membrane channel complexes and modulate the ionic conductance through the channels.[15]

TPM is rapidly and almost completely absorbed after oral administration. Its plasma concentration increases linearly with the increasing dose. The metabolism of TPM depends on hepatic P450 microsomal enzymes; therefore, its clearance is increased in the presence of enzyme-inducing antiepileptic drugs (AEDs) resulting in reduced TPM concentrations. It readily penetrates the central nervous system and nearly 70% to 80% is eliminated unchanged in the urine. The half-life is 21 hours with normal renal function and the time to steady state is 4-5 days.[17]

After initial evidence from open-label studies demonstrated efficacy,[18] the largest multicenter, randomized, double-blind, placebo-controlled trials ever conducted in migraine prevention confirmed the usefulness of this drug.[19,20] In both trials, participants were given varying doses of TPM or placebo. The best results were achieved at a dose of 100 mg or 200 mg, with no difference in efficacy observed between the 2 doses. Participants experienced a significant reduction in the frequency of migraine headaches, number of migraine days, and use of acute medications. On the basis of information about efficacy and tolerability, 100 mg/day of TPM should be the initial target dose for most patients, a lower dose than that used to treat epilepsy. The most common adverse events were paresthesias, fatigue, loss of appetite, nausea, diarrhea, weight loss, and taste perversion. TPM is currently considered a first-line migraine preventive drug and should especially be considered a preferred treatment for all patients who are concerned about gaining weight, who are currently overweight, or who have coexisting epilepsy.

TPM may be useful for pediatric migraineurs as well. Campistol and colleagues[21] evaluated 24 patients aged 6-14 years in a 4-month trial, observing efficacy and safety of TPM with a mean dose of 3.5 mg/kg/day after titration. A significant decline in severity and duration of attacks was shown with good/excellent impressions of efficiency. Two patients withdrew because of paresthesias or lack of efficacy.
Tiagabine

Tiagabine (TGB) is an effective add-on therapy for partial seizures. TGB inhibits the neuronal and glial reuptake of GABA and therefore enhances GABA-mediated inhibition. TGB does not induce or inhibit the function of hepatic enzymes and does not displace tightly protein-bound drugs, such as carbamazepine, theophylline, warfarin, and digoxin. Total and unbound TGB concentrations are increased in patients with hepatic dysfunction but are unaffected in patients with renal failure.[22]

TGB was initially studied in patients with refractory migraine,[23] with doses titrated to 4 mg, 4 times daily. In an open-label study of 41 migraine patients who had been previously treated with divalproex and discontinued therapy because of adverse events or relative lack of efficacy, Freitag and colleagues[24] used a mean dose of 10 mg/day. In this study, 5 patients experienced a remission of their migraine attacks, and 33 of the 41 studied had at least a 50% reduction in their attacks. The reported side effects, usually mild to moderate in severity and almost always resolving without medical intervention, included dizziness, asthenia (fatigue or generalized muscle weakness), nervousness, tremor, trouble concentrating, mental lethargy, slowness of thought, depression, aphasia, and abdominal pain.[24] The drug is not a standard treatment for migraine and does not carry an FDA indication for migraine.
Levetiracetam

Levetiracetam (LCT) is a new AED of unknown mechanism of action, although it has proved to be a broad-spectrum anticonvulsant in animal models.[25] It is rapidly and nearly completely absorbed after oral administration; peak serum concentrations are achieved within 2 hours, and daily doses are linearly related with plasma concentrations. LCT is metabolized primarily by hydrolysis of the acetamide group to the inactive carboxylic derivative and it is poorly protein-bound (< 10%).[26] The metabolic degradation of LCT is independent of the hepatic system of cytochrome P450, and therefore is not affected by the concomitant use of other AEDs. In children as well as in adults, steady state is achieved after 2 days of twice-daily dosing.

Anecdotal evidence suggests the usefulness of LCT in the prevention of migraine.[27,28] A recent study assessed LCT as prophylaxis of transformed migraine. Mean headache frequency per month at baseline was 24.9 and a significant reduction of headache frequency was obtained in 1 month (19.4, P < .001), 2 months (18.4, P < .001), and 3 months (18.0, P < .001).[29] The most common side effects reported in these initial clinical trials included fatigue or tiredness, somnolence, dizziness, and infection (common cold or upper respiratory tract infection).

Recently, the efficacy and safety of LCT for pediatric migraine was evaluated in a population of 30 children or adolescents aged 6 to 19 years (mean 12.9 years). This was a 10-week, open-label study. Among the 19 patients who completed the study, 6 patients experienced at least a 50% reduction in headache frequency and severity; 8 had at least 75% improvement; 3 became headache-free; and 2 developed worsening headaches. In 16 of the participants, disability decreased and quality of life improved, evaluated by PedMIDAS. One patient reported delusions and violent behavior; 1 patient developed a seizure disorder; 5 patients did not comply; and 4 withdrew because of lack of efficacy.[30] Zonisamide

Zonisamide (ZNS) is a sulfonamide derivative that is structurally and chemically unrelated to other AEDs. It has been used for adjunctive therapy of partial seizures, and it is rapidly and nearly completely absorbed after oral administration with negligible first-pass metabolism.[31] ZNS is unaffected by tightly protein-bound drugs, is binding to plasmatic proteins between 40% and 60%, and does not affect the protein binding of other drugs. The plasma half-life of ZNS in healthy volunteers after a single oral dose ranges from 50 hours to 68 hours, but in the presence of enzyme-inducing AEDs, it decreases by approximately 50%.[31-33]

ZNS presents a unique combination of pharmacologic actions: It blocks voltage-dependent sodium and T-type (but not L-type) calcium channels; reduces glutamate-mediated excitatory neurotransmission; inhibits excessive nitric oxide (NO) production, scavenging hydroxyl and NO radicals; and inhibits carbonic anhydrase. All of these mechanisms may play a role in headache and pain modulation, possibly via neuronal stabilization.[31-34]

ZNS was studied for migraine prevention in 2 open-label trials presented. The first evaluated 33 patients with mixed headache disorders and refractory migraines.[35] Most had not responded to at least 2 previous preventive agents. ZNS was started at a dosage of 100 mg at bedtime every third day for 4-5 doses. The dosage frequency was then increased to every other day for another 4-5 doses, followed by the same dosage on a daily regimen. Dosage was adjusted upward every 2-3 weeks and in some cases reached as high as 600 mg/day. A total of 18% of the participants reported a 65% or better reduction in the frequency of migraine attacks and other headaches; 24.2% reported a 25% to 50% decrease in the same parameter; and 27% did not respond or were noncompliant with the protocol.

In the second study,[36] 34 patients with migraine with and without aura who were refractory to other preventive therapies received an initial dosage of 100 mg of ZNS daily, which was titrated as tolerated to 400 mg daily. Headache severity was significantly reduced as well as the other headache measures. The side effects reported included paresthesia, fatigue, anxiety, and weight loss. Agitated dysphoria and difficulty concentrating were also observed.

The tolerability of ZNS is favorable if titrated slowly. The most common side effects reported are somnolence, ataxia, anorexia, confusion, abnormal thinking, nervousness, fatigue, and dizziness. ZNS is weight-neutral and some patients report weight loss. Reports on development of kidney stones, leukopenia, and abnormal liver enzyme levels have been described.[32,34] Petasites

Petasites is an extract from the plant Petasites hypridus (butterbur), which is a perennial shrub found throughout Europe and parts of Asia and North America. It has been used medicinally for centuries and during the Middle Ages was used to treat plague and fever. In the 17th century, butterbur was used frequently in treating cough, asthma, and skin wounds. In addition, petasites has been reported to inhibit peptide-leukotriene biosynthesis, possibly through calcium channel regulation.[37,38]

The efficacy of petasites in migraine prevention was studied in 2 trials. A small randomized, double-blind, placebo-controlled trial reported that a low dose of petasites, 50 mg twice daily, significantly reduced the number of migraine attacks per month and the number of migraine days per month.[39] In a larger double-blind, 5-month trial, Lipton and colleagues[40] randomized patients to receive either petasites 50 mg or 75 mg twice daily, or placebo. Compared with placebo-treated patients, the 4-month mean attack count was reduced by 48% in patients treated with petasites 75 mg twice daily, 34% with petasites 50 mg twice daily, and 26% with placebo (P < .01). All the other parameters showed similar results. The investigators concluded that petasites 75 mg twice daily may be an effective alternative preventive treatment for migraine.[40]

The tolerability of this herbal product seems to be good because side effects from petasites extracts have not been reported. However, the plant’s pyrrolizidine alkaloids are thought to cause liver damage and to be carcinogenic in animals.[38] Therefore, extracts are commercially available in which the pyrrolizidine alkaloids have been removed. There are no known interactions with either pharmaceutical or over-the-counter anti-inflammatory agents; however, use of petasites extracts during pregnancy and lactation is contraindicated.[40] Carvedilol

The use of beta blockers for migraine prevention is not new. The evidence for the use of this pharmacologic class was well established with propranolol, timolol, atenolol, and nadolol. The use of novel beta blockers, such as carvedilol, for the prophylactic treatment of migraine is a new concept because it offers additional alpha-1 blocking and antioxidant properties. This nonselective alpha-1 and beta-1 antagonist reduces blood pressure by reducing peripheral vascular resistance with no alteration of heart frequency or cardiac debit.[41] The results are a very favorable adverse event profile, which may represent an appeal in migraine prevention because traditional beta blockers have limiting side effects.

Carvedilol was initially studied for migraine in a prospective, open-label trial involving 76 patients. The dosages were titrated from 3.125 mg/day to 6.25 mg twice daily over 2 weeks. After 6 weeks of maintaining a stable dosage, patients were required to choose between keeping the 6.25 mg twice-daily dosage, increasing it to 12.5 mg twice daily, or decreasing it to 3.125 mg twice daily. Of the 68 patients who completed the study, 40 (59%) experienced a 50% reduction in monthly migraine attack frequency at the third month of treatment. Ten (15%) didn’t present any significant response, and 18 (26%) withdrew because of lack of efficacy, or as a result of adverse events, including diarrhea, insomnia, nausea, dizziness, and myalgias.[42] Tizanidine

Tizanidine hydrochloride is an alpha2-adrenergic presynaptic agonist that inhibits the release of norepinephrine in the brainstem and spinal cord. The antinociceptive effect does not involve the opioid system but is expressed on the alpha-adrenergic system at the alpha receptors located at the substantia nigra pars compacta.[43] Tizanidine is not an antihypertensive medication but contains several pharmacologic similarities to clonidine, another alpha2-adrenergic presynaptic agonist that has been advocated for migraine prophylaxis. Studies with cats demonstrated an inhibitory effect on vasoconstrictor and vasodilator responses to noradrenaline, adrenaline, isoprenaline, and angiotensin.[44]

The efficacy of tizanidine in headache was shown in a controlled study involving the treatment of chronic daily headache, especially in chronic migraineurs.[43] In addition, an open study of 220 patients demonstrated efficacy in both migraine and chronic tension-type headache,[46] which makes this drug attractive as a possible prophylactic treatment of episodic migraine and tension-type headache.
Quetiapine

Quetiapine (QTP) is a dibenzothiazepine derivative classified as an atypical antipsychotic drug with a low affinity for dopaminergic D1 and D2 receptors but high affinity for D4 receptors. QTP has an interesting characteristic of presenting antagonistic properties at many neurotransmitter receptors. In addition, it has interesting, more pronounced effects on mesolimbic than on nigrostriatal dopaminergic pathways, which results in better tolerability with regard to extrapyramidal symptoms.[47] QTP represents a new hope for migraineurs because it also possesses high affinity for 5-HT2 receptors, partial agonistic activity at 5-HT1A receptors, and a blocking activity at alpha1-adrenergic receptors with a consequent potential for migraine prevention.[47,48] QTP has a short half-life of 2-3 hours, requiring a twice-daily regimen for schizophrenic patients. It presents a favorable side-effect profile if titrated gradually, but somnolence and dizziness may be common. In 7% of the patients, orthostatic hypotension may occur. Its pharmacokinetics is not affected by sex, ethnic group, cigarette smoking, or body weight.[49]

The role of QTP in migraine was studied in 24 migraineurs who had a history of not responding at least to 2 agents. QTP was initiated as an add-on therapy at a dose of 25 mg daily with a progressive titration to a maximum of 150 mg daily. At an average dose of 75 mg daily, 21 of the 24 patients showed significant improvement in either frequency or severity, or both, of migraine. Disability, evaluated by the Migraine Disability Assessment (MIDAS) score, improved by at least 1 grade in 18 patients, with none presenting serious side effects or extrapyramidal symptoms. One patient discontinued the drug because of sedation.[49] The clinical impression is that QTP may represent a very important resource for patients with refractory migraine or patients with psychological disturbances.[48,49] Botulinum Toxin

Botulinum toxin (BTX) is a bacterial neurotoxin approved for the treatment of strabismus, blepharospasm, and hemifacial spasm; BTX also has been safely used for spasticity, tremor, dystonia, and other neuromuscular disorders of inappropriate muscular contraction. BTX has also been used to reduce wrinkles and hyperfunctional lines of the face. BTX causes long-term cholinergic blockade at the neuromuscular junction, which is thought to be responsible for its chemodenervating action and the therapeutic effect causing muscle paresis or paralysis. In addition, it has antinociceptive properties, an effect unrelated to its inhibition of the muscle contraction.[50] BTX may work in migraine through the suggested inhibition of substance P, calcitonin gene-related peptide (CGRP), and glutamate.[50,51]

BTX has been evaluated in open-label trials and large multicenter studies.[52,53] Silberstein and associates[53] examined the safety and efficacy of BTX in migraine prevention with a double-blind, vehicle-controlled design. A total of 123 patients from 12 headache centers were recruited in this double-blind, randomized, placebo-controlled (vehicle-controlled), parallel-group prospective study. The requirements of the protocol included a 1-month baseline, an injection visit, 3 monthly postinjection visits, and completion of a daily headache diary. Patients with migraine (with or without aura) who had experienced an average of 2-8 moderate-to-severe migraines per month during the 3 previous months were eligible. Patients were randomized to 1 of 3 groups: BTX 25 U or 75 U, or vehicle. The sites of the injections were symmetric into the glabellar, frontalis, and temporalis muscles. Participants kept diaries for 3 months post injection.

The group of patients that received 25 U of BTX received a significantly better performance than the vehicle in all endpoints. The 75-U BTX treatment group was significantly more improved than the vehicle group on patient global assessment for days 31-60 but not other parameters. BTX was well tolerated, but the group that was injected with 75 U showed significantly more treatment-related adverse events than vehicle. The conclusion of the study was that pericranial injection of BTX, 25 U, is effective for the treatment of migraine. The adverse effects, usually transient and mild, included blepharoptosis, diplopia, and injection-site weakness, which is an expected drug effect.

In other study, BTX reduced the number of headache days 60 patients with either chronic tension-type headache or chronic migraine compared with placebo, but this difference was not statistically significant.[54] Results from another large multicenter trial of BTX in the preventive treatment of chronic daily headaches, already conducted, are anxiously awaited.
Compounds in Development

The ideal migraine drug should be effective both for prophylaxis and for acute treatment. The need for a well-tolerated preventive drug that can significantly reduce or eliminate migraine attacks, preferentially acting on different biological systems, is obvious. Cost is an issue as well. The probability that such a drug will be developed in the near future is low, however, because the nature of migraine is multifactorial and still emerging, and because patients’ central nervous system responses are so variable. Although recent additions to the migraine pharmacologic arsenal demonstrate multiple effects on pathophysiologic mechanisms of migraine, a definitive drug is still far from reality.

Progress in finding new effective treatments for acute migraine has been more promising. Several drugs and potential targets are under development and will be highlighted in the next section.
Drugs Acting on 5-HT (Serotonin) Receptors

The 5-HT1B/1D agonists, or triptans, target the trigeminovascular system. They are vasoconstrictive medications, an action mediated through the 5-HT1B postsynaptic receptor subtype.[55] Because of the presence of 5HT1B receptors on peripheral and coronary vascular beds, the potential for serious adverse vascular events precludes the unlimited use of triptans because of safety concerns in subjects at a higher risk for cardiovascular events.[56] Theoretically, drugs targeting 5-HT1D, but not 5-HT1b, receptors could be effective without vasoconstrictive effects. In addition, 5-HT1F receptors appear to play an important role in migraine attacks. Several emerging migraine medications target these receptors subtypes without activity at the 5-HT1B receptor.[57] Two agents acting primarily on 5-HT1D and/or 5-HT1F receptors are PNU-142633 and the LY334370.

PNU-142633 is a highly selective 5-HT1D agonist with at least 1000-fold selectivity for the 5-HT1D receptor compared with the 5-HT1B receptor.[58] Animal model studies suggest that PNU-142633 blocks the neurogenic inflammation and the rise in trigeminal nucleus blood flow normally elicited by stimulation of trigeminal afferent fibers, with no evidence of vasoconstriction on carotid, meningeal, or coronary arteries.[58] Its safety and tolerability were demonstrated in a phase 1, single-dose, double-blind study. Thirty-nine patients received doses from 1 mg to 100 mg, with no serious adverse events reported; the most common side effects were headache and dizziness.[58] However, another study using a 50-mg oral dose of PNU-142633 failed to show a significant treatment effect compared with placebo.[59] With regard to safety issues, 3 of the 34 patients receiving PNU-142633 experienced QTc interval prolongation on electrocardiography and 2 of these reported chest pain. Definite conclusions about this study are of questionable validity because PNU-142633 was developed with gorilla 5HT1D receptors, and differences in relative potency on the 5-HT1D receptors must be considered. Another 5-HT1D agonist, PNU-109291, did not demonstrate efficacy in preclinical models of migraine. Further studies are still under way with this compound.[60]

Most of the triptans currently in use were shown to exert an effect at cloned human 5-HT1F receptors; in addition, in animal models, selective 5-HT1F agonism inhibited neurogenic inflammation.[61,62] Recently, a selective 5-HT1F receptor agonist, LY334370, has been developed. In phase 1 studies, LY334370 was not associated with evidence of cardiac ischemia on electrocardiogram. However, intravenous doses up to 20 mg and oral doses up to 200 mg caused somnolence, mild-to-moderate asthenia, dizziness, and paresthesias.[63] In a double-blind, randomized, placebo-controlled study, migraine sufferers were randomized to receive placebo or 20 mg, 60 mg, or 200 mg of LY334370.[64] Headache response, pain-free, and sustained pain-free rates after 2 hours were significantly better in the 60-mg and 200-mg treatment groups, compared with those receiving placebo. The patients receiving 200 mg experienced the best results; 71% of these patients had headache response at 2 hours and 38% achieved pain-free status. In all, 33% demonstrated sustained pain-free response at 24 hours. The tolerability was troublesome; however, 80% of patients receiving the 200-mg dose reported at least 1 adverse event. In addition, a high toxicity in animal studies was observed and the development of the drug was interrupted. Further studies with other agents of this pharmacologic class are in process.[64] Adenosine Receptors

Adenosine has an established antinociceptive effect in humans. Recent findings in rats suggest that the both chronic and acute analgesic effects may be mediated by adenosine A1 receptors within the spinal cord.[65] However, despite the existence of the A1 receptor protein in human trigeminal ganglia, the relevance of these findings for migraine is still unknown.[66] Currently, 2 selective A1 receptor agonists, GR79236 and GR190178, are under development. In studies with cats, these compounds inhibited trigeminal nociceptive transmission and the peripheral release of CGRP in the cranial circulation and at the central trigeminal synapse. In addition, in the rat model, GR79236 inhibited the firing of second-order neurons in response to electrical stimulation of nociceptive afferents of the trigeminal nucleus caudalis.[67,68] This process, if operative, may prevent activation of central trigeminal neurons.[69] In fact, measured by suppression of nociceptive blink reflex, GR79236 has been demonstrated to effectively inhibit trigeminal nociception in humans, which supports its potential as an acute migraine treatment.[70] Vanilloid Receptors

The vanilloid type 1 (VR1) receptors are located on small and medium-sized neurons, which are either unmyelinated C-fibers or thinly myelinated A-delta fibers. VR1 receptors also are present on neurons in the human trigeminal ganglia.[71] Capsaicin is the best known vanilloid and activates afferent fibers involved in nociceptive transmission as well as in neurogenic inflammation. This activation leads to rapid desensitization, and loss of sensitivity to heat and chemical stimulation with consequent inability to release the neurochemicals involved in neuronal transmission and inflammation, such as substance P and CGRP. In addition, intravenous capsaicin promotes the release of the proinflammatory neuropeptides from trigeminal neurons and has been shown to cause dilatation of the vasculature of rat dura.[72] The possibility that VR1 receptor activation results in CGRP-induced vasodilatation at the trigeminovascular junction have lead to the study of a capsaicin derivative as a potential antimigraine drug. Civamide is a cis-monomer of capsaicin with vanilloid agonistic properties as well as a neuronal calcium channel effect. Its antimigraine action may be through the release of neurotransmitters to meningeal and dural blood vessels, reducing neurogenic inflammation, peripheral sensitization, and headache pain.[73]

The possible efficacy of intranasal civamide in migraine was studied in a non-placebo-controlled study of 34 patients with migraine. In all, 55% of the patients in whom nasal burning and lacrimation occurred frequently achieved headache relief at 2 hours. No systemic side effects were reported with the intranasal use of civamide.[73] CGRP

CGRP is a neuropeptide found within cell bodies of the sensory terminals in the trigeminal nerve. Along with other neuropeptides, such as substance P and neurokinin A, it innervates the cerebral vasculature and may exert a counterbalance effect on cerebrovascular contraction. This action, which is induced by dilatation of cerebral vessels, increasing cerebral blood flow and mediating the trigeminal reflex, relates to CGRP receptors existing in various cerebral and cranial arteries.[74] In addition, in animal models, stimulation of trigeminal ganglion fibers results in release of CGRP leading to neurogenic vasodilation.[75]

CGRP has an important role in migraine. CGRP levels are increased in the external jugular venous blood during spontaneous migraine attacks or following electrical or chemical stimulation, with normalization of levels after treatment with sumatriptan.[76,77] Furthermore, infusion of human CGRP in migraineurs induces migrainelike headache.[76] The investigation of the CGRP role in migraine has led to the development of CGRP antagonists, which are still in preclinical phase trials.

BIBN4096BS is a small molecule with a high affinity and specificity for the human CGRP receptor. It is a nonpeptide CGRP-receptor antagonist.[78] Healthy volunteers were tested to evaluate the safety and tolerability of BIBN4096BS. They were randomized to receive intravenous placebo or drug in doses ranging from 0.1 mg to 10 mg. There were no clinically relevant changes in pulse rate, blood pressure, respiratory rate, electrocardiography, laboratory tests, or forearm blood flow. Fatigue and paresthesias were the most reported adverse events.[79] The first study in migraine was carried out with a multicenter, randomized, double-blind design.[80] The primary endpoint was headache efficacy (severe or moderate headache at baseline to mild or no headache at 2 hours). The 2.5-mg dose resulted in a response rate of 66%, compared with 27% for the placebo. Other endpoints, such as pain-free rate at 2 hours; sustained response over 24 hours; recurrence of headache; improvement of nausea, photophobia, phonophobia, andfunctional capacity, were also evaluated and demonstrated the superiority of BIBN4096BS over placebo. A total of 25% of the patients receiving the 2.5-mg dose reported adverse events, consisting mostly of paresthesias and no serious adverse events.[80] Drugs Modulating Glutamate

Glutamate is the major excitatory neurotransmitter in central nociceptive pathways and has been implicated in the pathophysiology of migraine. In animal models, glutamate promotes excitation of neurons at the trigeminal nucleus caudalis. In addition, noxious stimuli trigger rising levels of glutamate in the trigeminal nucleus caudalis.[81] The glutamate receptors may be a G-protein-coupled receptor (metabotropic) (such as mGlu receptors groups I, II, or III) or ion-forming channel (ionotropic) receptors (such as NMDA, non-NMDA [AMPA], and kainite [KA] types).[82] The path to develop ionotropic NMDA receptor antagonists has been frustrating because of its bad tolerability profile.[83] However, non-NMDA AMPA/KA antagonists, such as LY293558, have shown promising preclinical performance.[84] The efficacy of LY293558 in migraine was evaluated recently in a pilot study in which 45 patients were enrolled and 44 completed the trial with response rates of 69% vs 25% of the placebo (P = .017). LY293558 has an acceptable tolerability profile, with visual distortions as the most prominent adverse event. Minor effects, such as dizziness and sedation, were also reported, and no serious side effects were described.[85] Drugs Acting at the NO Synthase

NO is a small molecule gas synthesized from L-arginine with potent vasodilator properties. NO is found in endothelial cells, granulocytes, platelets, and the brain. In the normal brain, endothelial and neuronal NO are expressed, but a third isozyme that synthesizes NO appears to be inducible in response to tissue damage or following nitroglycerine administration.[86] The relationship of nitric oxide synthase (NOS) inhibition on neuronal activity in the trigeminal nucleus has been demonstrated in animal models. The infusion of a NOS inhibitor significantly reduced neuronal activity, suggesting that NO may play an important role in sensitized neurons in the trigeminal nucleus. In addition, the administration of the exogenous NO donor nitroglycerin in rats induces delayed plasma protein extravasation in dura mater. Furthermore, the cortical spreading depression, which releases CGRP from nerve terminals triggering the migraine cascade, also releases NO.[87] These observations along with the knowledge that intravenous nitroglycerine infusion causes a migraine attack in migraineurs but not in nonmigraine controls suggests the important role of NO in migraine.[88]

Thus far, LNMAH 546C88 is the only NOS inhibitor being studied. This agent was administered intravenously to 15 patients with migraine, and compared with 14 subjects who received placebo. Ten of the 15 patients experienced relief 2 hours after the infusion compared with 2 of 14 in the placebo group.[89]

Although well tolerated, LNMAH 546C88 did not alleviate histamine-induced migraine, but in a randomized, double-blind, crossover trial of 16 patients with chronic tension-type headache (patients were assigned intravenous infusion of 6 mg/kg L-NMMA or placebo for 2 days separated by at least 1 week in a randomized order), L-NMMA reduced pain intensity on the visual analog scale significantly more than placebo. These preliminary results suggest that NOS inhibition may represent a safe and effective way of treating acutely primary headache in which NO mechanisms may be involved.[90,91] Potential Development Issues

Although many of the drugs presented in this review provide effective migraine relief, they do not approach having the prerequisites of an ideal antimigraine medication. With the exception of sodium divalproex and TPM, most of the current prophylactic agents have not been studied in randomized controlled trials with an acceptable number of subjects. We look forward to a drug, or at least a strategy of treatment, that can act on the glutamatergic-GABAergic transmission imbalance in addition to exerting a modulating effect on the serotonergic system.

Although effective, most of the current options for acute therapy do not offer consistent and fast pain-free endpoints in all patients. Acting simultaneously in different pathophysiologic mechanisms of a migraine attack, such as inflammation and “low serotonin,” is an attractive goal. In addition, developing a serotonergic agonist devoid of vasoconstrictor effects (ie, no 5-HT1B action) would represent a significant advance, as would an agent that acts on different targets as the CGRP receptor.

The importance of rational polytherapy is indisputable. Combining pharmacologic agents with actions on specific, different neurotransmitter systems and targets is a necessary goal. As a multifactorial disease, migraine should be managed through multimodal pharmacotherapy, which currently cannot be provided by a single agent.
Conclusion

The possibility of better modulating the imbalance between central neurotransmitters that occurs with migraine has created an exciting search for new pharmacologic sites. The use of animal models to predict human effects has not been as successful as expected but more clinically predictive pharmacologic models are being developed. Drugs acting on the early stages of migraine and nonvasoactive therapies are in the late stages of development. Neuromodulators for the prevention of multiple mechanisms related to migraine are already available. Obtaining synergies by combining agents with different sites of action is a valuable approach. The better use of available drugs, beyond conservative monotherapy, may represent an important strategy for helping migraine patients until better drugs are developed.
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