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Migraine
Migraine headache is an episodic headache disorder. It is a
common condition with a prevalence of 17.6% in females and
5.7% in males. An American Migraine Study estimated that 23
million persons older than 12 years of age have severe
migraine headaches; however, this condition is under-treated
and under-diagnosed worldwide. Not all headache sufferers seek
medical attention, but those who do generally consult family
practitioners, internists or pediatricians, ophthalmologists,
and neurologists The social and economic effects of migraine
are staggering--perhaps $2 to $17.2 billion are lost in
productivity per year. The treatment of migraine has not only
medical but also serious economic and social implications.
Thus, primary-care physicians should be well versed in the
diagnosis and treatment of migraine. Rational migraine
treatment necessitates an accurate diagnosis, identification
and removal of potential triggering factors,
non-pharmacological and if needed pharmacological
intervention. Both the avoidance of migraine trigger factors
and the use of non-pharmacological therapies have a part to
play in overall migraine management (1). Effective management
also includes establishing realistic expectations, patient
reassurance, and education (2).
SYMPTOMS COMPLEXES IN MIGRAINE:
Any attempt to explain the pathophysiology of migraine has to
account for the following components of the attack:
Premonitory Symptoms(Aura)
The aura may last 20 to 30 minutes and may include one or
more of the following:
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Mood changes
(commonly a sense of elation associated with
hyperactivity) |
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Increased
appetite (particularly for sweet foods). |
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Excessive
yawning may precede migraine by as long as 24 hours, on at
least some occasions, in about one third of migraine
patients. |
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Blindspots (scotomata)
or visual field cuts may have distinctive scintillations
or fortification patterns around them. Typically, the
scotomata clear as the headache appears. |
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Sensory
hyperacuity ( light may be perceived as dazzling or may
provoke pain, sounds may appear unnaturally loud, and
smells may be more intense during (or even before) the
headache phase). |
Focal Neurological Symptoms
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These
neurological symptoms may arise from the cerebral cortex,
brain stem, or cerebellum and may anticipate the onset of
headache as in the prodromal phase of classic migraine or
may appear during the headache phase. |
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Focal
neurological symptoms of classic migraine, whether arising
as a prodrome or developing during the headache phase, are
accompanied by diminished cortical perfusion of the
appropriate part of the opposite cerebral hemisphere. On
some occasions a wave of hypo-perfusion may advance slowly
over the cortex in association with a slow march of visual
or other neurological symptoms whereas on other occasions
it may persist as a local or diffuse cortical oligemia. It
is clear that the presence or absence of headache does not
depend on changes in cerebral blood flow. |
Headache
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It is
unilateral in two thirds of patients. It commonly starts
as a dull ache at the occipito-nuchal junction, or in one
temple and then spreads over that side of the head or the
whole head or may remain localized as a "bar of
pain" extending from the eye to the occiput. The pain
is usually constant and unremitting but assumes a
pulsatile or throbbing quality when sever, it may
consistently affect the same side of the head or may move
from side to side, even in the one migraine episode. Pain
may radiate down the neck to the shoulder or, in some
cases, to the arms and even the leg on the same side of
the body, suggesting that the spinothalamic tract has
collaborated with trigeminal pathways in the production of
pain. |
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The frontal
branches of the superficial temporal artery become
distended in about one third of patients, venous
engorgement may be seen, and heat loss increases from the
affected area. Most patient appear pale and "dark
under the eyes" as the headache worsens, although
exceptional patients flush before or during the attack.
Sensitivity of the scalp to touch and muscular
hyperalgesia may develop during, and outlast, the headache
phase. |
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However
headache of migraine is not necessarily associated with
vascular pulsation, dilation of extra-cranial arteries or
increased cerebral perfusion. |
Gastrointestinal symptoms
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Nausea
sometimes precedes the onset of headache but commonly
evolves as the attack progresses and may culminate in
vomiting. Diarrhea is associated in about 20%of patients.
Such gastrointestinal symptoms are mediated by an enzyme,
dopamine beta-hydroxylase(DBH) that is the final enzyme in
the synthesis of noradrenaline. |
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PAIN-SENSITIVE
CRANIAL STRUCTURE |
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The
foundation for any study of the causes and treatments of
headache is knowledge of the pain-sensitive structures and
pain-conducting pathways within the cranium. |
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All
available evidence supports an orderly somatotopic
representation of the supratentorial pain-sensitive
meningeal and vascular structures within the trigeminal
system. Pain sensation from posterior fossa structures is
carried centrally by the vagus nerve, the upper three
cervical nerves, and possibly by trigeminal afferents as
well. |
THE ORIGIN OF MIGRAINE HEADACHE
The bones of the skull and brain substance are insensitive to
pain because they lack pain sensitive nerve fibers.
Pain is referred to the frontotemporal area of the skull, from
the following structures:
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The dura. |
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The
intracranial segment of the internal carotid artery. |
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The proximal
few centimeters of the anterior and middle cerebral
arteries. |
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A portion of
the cerebral veins and venous sinuses. |
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The middle
meningeal artery. |
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The
superficial temporal artery. |
The previously mentioned structures contain
pain sensitive nerves with the nociceptors at their ends. The
latter can be stimulated by stress, muscular tension, dilated
blood vessels and other triggers of headache. Once stimulated,
the nociceptor sends a message up the length of the nerve
fiber to the nerve cells in the brain, signaling that a part
of the body hurts. In periarterial fluid sampled during
migraine headache, a polypeptide was found, named "neurokinin".
This bradykinin-like substance was postulated to set up a
sterile inflammatory response in the vessel, which became
pain-sensitive, and is responsible for the transmission of the
pain impulse to the brain nerve cells.
Platelets aggregation takes place in subgroups of migraine
patients and may be a factor in the vascular thrombosis of
"complicated migraine". However the blood platelets in most
patients seem to be remarkably normal and their role in
migraine is probably limited to aggregation in some instances
and to serotonin release which potentiats the pain-producing
effect of bradykinin.
Dilation of scalp arteries in this area contributes to the
intensity of headache, and compression of the temporal artery
eases the pain.
Platelet serotonin content increases before migraine attacks
and falls during the headache phase in most migraine patients.
A serotonin-releasing factor was found present in the blood
during migraine headache. The main metabolite of serotonin,
5-hydroxyindoleacetic acid, is excreted in excess in the urine
of some patients during migraine attacks. However it seems
unlikely that the amount of serotonin released from platelets
during migraine headache would be sufficient to cause any
vascular constriction, but it may possibly combine with
bradykinin to render the arterial walll sensitive to painful
dilation. It has been postulated that free fatty acids might
be responsible for the release of serotonin from blood
platelets in migraine.
Blood histamine is significantly increased after migraine
headache. It is claimed that liberated histamine might
contribute to the vascular component of migraine.
Prostaglandins, long-chain unsaturated fatty acids derived
from arachidonic acid, have potent constrictor and dilator
effects. During migraine headache, plasma levels of PGE1 do
not alter, but the level of PGE2-like substances has been
shown to fall significantly, in contrast with its elevation
found in cluster headache.
THE MECHANISMS OF MIGRAINE
Hypotheses for the mechanisms of many aspects of migraine have
been extensively studied (3). The aura symptoms are, most
likely caused by a mechanism similar to spreading excitation
and depression (4).
It is has been believed that migraine attack is a specific
reaction pattern to an episode of focal cerebral hypoxia. This
hypothesis holds that any type of focal brain hypoxia (and
thus not only a vasospasm) may provoke a migraine attack.
Indeed, as hypoxia is a result of an imbalance between energy
supply and energy use, the former can be decreased and/or the
latter be increased. Spreading cortical depression, leading to
the aura, is believed to be a consequence of brain hypoxia
occurring in classical migraine. There are no genuine
differences between classical and common migraine, according
to the cerebral hypoxia theory. The latter theory may improve
our understanding of the mode of action of antimigraine drugs.
Certain calcium entry blockers have a direct protective effect
on brain hypoxia, but some other pharmacotherapeutic
approaches may also prevent cerebral hypoxia via an effect on
brain metabolism, vasomotion or platelet behavior (5). It has
been postulated that the classic migraine is both spreading
cortical depression and localized ischemia linked in a vicious
cycle by potassium induced vasoconstriction. The cycle can be
initiated by any event that raises the local cortical ECF
(extra-cellular fluid) potassium concentration to
approximately 20 mM. Such an event could be a localized burst
of activity of a group of cells, localized metabolic
impairment, or a transient reduction in blood flow to a region
of the cortex. Once this level of potassium concentration is
reached, it may result in localized depolarization of neurons,
releasing more potassium into the ECF. As the concentration
continues to rise, vasoconstriction becomes more intense,
perpetuating the cycle that results in localized depression of
cortical neuronal activity and ischemia. The condition is
propagated to adjacent regions of the cortex by diffusion and
glial-mediated spread of potassium (6).
Neuronal hyperexcitability between attacks may be due to:
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Mitochondrial
disorder. |
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Magnesium
deficiency. |
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Abnormality
of presynaptic calcium channels. |
Like many others neurological diseases,
mitochondrial involvement, by means of abnormalities in
cerebral oxidative metabolism, may play a role in migraine(7).
The importance of magnesium in the pathogenesis of migraine
headaches is clearly established by a large number of clinical
and experimental studies. However, the precise role of various
effects of low magnesium levels in the development of
migraines remains to be discovered.
Magnesium concentration has an effect on:
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Serotonin
receptors. |
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Nitric oxide
synthesis and release. |
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A variety of
migraine related receptors and neurotransmitters. |
The available evidence suggests that up to 50%
of patients during an acute migraine attack have lowered
levels of ionized magnesium. Infusion of magnesium results in
a rapid and sustained relief of an acute migraine in such
patients. Two double-blind studies suggest that chronic oral
magnesium supplementation may also reduce the frequency of
migraine headaches (8). Increased tissue levels of taurine, as
well as increased extracellular magnesium, could be expected
to:
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Dampen
neuronal hyperexcitation. |
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Counteract
vasospasm. |
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Increase
tolerance to focal hypoxia. |
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Stabilize
platelets. |
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Taurine may
also lessen sympathetic outflow. |
Thus it is reasonable to speculate that
supplemental magnesium taurate will have preventive value in
the treatment of migraine.
THE HUMORAL-VASCULAR THEORY OF MIGRAINE
The humoral-vascular theory postulates that circulating
vasoactive amines constrict the cortical microcirculation,
thus causing the neuralgic symptoms and signs classic of
migraine and that a subsequent phase of dilatation
(predominantly extracranial ) is responsible for headache.
Dilatation of extracranial, middle meningeal, or cerebral
arteries is thought to cause pain in migraine because the
vessel wall has been sensitized by the adsorption of serotonin
released from platelets and the periarterial accumulation of
histamine and bradykinin, causing sterile inflammatory
response around extracranial vessels. In case of normal immune
system Opioid-containing immune cells migrate preferentially
to inflamed sites, where they release beta-endorphin which
activates peripheral opioid receptors to inhibit pain. This
immune response is altered in migraine patients. Immunocyte
recruitment is a multistep, sequential engagement of various
adhesion molecules located on immune cells and vascular
endothelium. Selectins mediate the initial phase of immunoctye
extravasation into inflamed sites. Anti-selectin treatment
abolishes peripheral opioid analgesia elicited either
endogenously (by stress) or by corticotrophin-releasing
factor. This results from a blockade of the infiltration of
immunocytes containing beta-endorphin and the consequent
decrease of the beta-endorphin content in the inflamed tissue.
These findings indicate that the immune system uses mechanisms
of cell migration not only to fight pathogens but also to
control pain in injured tissue. Thus, pain is exacerbated by
measures inhibiting the immigration of opioid-producing cells
or, conversely, analgesia might be conveyed by adhesive
interactions that recruit those cells to injured tissue (9).
A significant reduction in peripheral blood mononuclear cell
beta-endorphin concentrations was observed in migraine
patients with and without aura. Altered transmitter modulation
to peripheral blood mononuclear cells may be the cause of this
alteration, which could be part of a more diffuse opioid
system derangement in migraine subjects (10). The life span
pattern of circulating peptide, beta-endorphin (B-EP) is
characterized by a progressive increase during prepuberal
development, by stable levels in adults with typical circadian
and monthly variations, and by a decrease in aging subjects.
The concomitant changes in the reproductive system suggested
the possible influence of gonads on B-EP plasma levels, as
confirmed by decreasing B-EP levels in gonadectomized humans
and rats. Headache, which is likely to occur concomitantly
with hormonal milieu variations, appeared to be associated
with a deficiency in the B-EP system, centrally and
peripherally, the lowest values being found in the protracted
forms of headache (11). The somatostatin-like (SLI), the
neuropeptide Y-like (NPY-LI), and the beta-endorphin-like
(BE-LI) immunoreactivities of cerebrospinal fluid (CSF)
obtained by suboccipital puncture, or plasma from patients
suffering from common migraine were analyzed. The SLI
concentration was tendentiously decreased in the migraine
patients during the attack-free period. During the migraine
attack the level of SLI was further decreased. Similar
alteration was found in the CSF BE-LI, while the BE-LI in the
plasma showed only a tendentious decrease in common migraine
patients. The NPY-LI did not change during the attack period
in the CSF or plasma. These findings may indicate the possible
role of somatostatin in the pathogenesis of common migraine,
and support earlier observations that beta-endorphin is
involved in the development in this disorder (12). Specific
chemical mediator release such as histamine and the
prostaglandins (PG2a or PGD2) associated with headaches has
been found in a few patients who were repeatedly challenged
with specific food (5).
Histamine is able to induce spontaneous-like headache attacks
in migraine and cluster headache subjects. Therefore, it has
been considered as a possible agent in the pathogenesis of
headache. Histamine desensitization is used for the treatment
of cluster and other chronic headaches like migraine with
interparoxysmal headache (13). A double blind,
placebo-controlled trial was performed to establish the
duration of action of antihistamines and their ability to
attenuate the adverse effects associated with histamine
release. It has been found that an adequate dose of
antihistamines is recommended to achieve appropriate
chemoprophylaxis (14).
Headache can be induced by histamine in wine sensitive
patients suffering from histamine intolerance, a disease
characterized by impaired histamine degradation based on
reduced diamine oxidase activity or a lack of the enzyme. As
supportive treatment, a vitamin B6 (pyridoxal phosphate)
substitution appears useful in histamine-intolerant patients
as pyridoxal phosphate seems to be crucial for diamine oxidase
activity. Histamine intolerance, based on reduced diamine
oxidase activity or a lack in the enzyme, causative for
wine/food-induced chronic headache. According to the
localization of diamine oxidase in the jejunal mucosa,
histamine intolerance is primarily a disease of intestinal
origin. A histamine-free diet is the treatment of choice in
histamine-intolerant patients suffering from chronic headache.
In addition, it is also important to avoid
diamine-oxidase-blocking drugs and alcohol which act as
inhibitors of diamine oxidase. As avoidance of histamine-rich
food is simple, inexpensive and harmless treatment,
histamine-containing food such as cheese and alcoholic
beverages should be labeled (15).
Platelets aggregation and the platelet release reaction are
caused by a plasma substance of low molecular weight, which
could be one or more of the free fatty acids liberated by
catecholamines secreted as part of a response to stress. A
reported case of acute promyelocytic leukemia and disseminated
intravascular coagulation presented with migraine with aura as
the first sign may support theories of platelet serotonin
involvement in the pathogenesis of migraine (16).
Endothelin-1 (ET-1) exerts powerful vasoconstrictive action.
The lower plasma level of ET-1 observed in the patients with
migraine is consistent with the pathogenesis of migraine,
further supporting the hypothesis that a lower ET-1 may be
closely related to marked vasodilatation following the
vasoconstriction (17).
THE NEUROGENIC THEORY OF MIGRAINE
This theory postulates that migraine headache involves
trigeminovascular and brainstem mechanisms. The ability to
trigger an attack may depend on a threshold of brain
excitability.
Monoamines have been considered to be the neurotransmitters
most likely to be involved in the mechanism of migraine
because blood levels of noradrenaline and serotonin fluctuate
with the course of headache. The newly acquired knowledge of
brain stem monoaminergic nuclei and their influence on
cortical activity and cerebral blood flow as well as their
participation in the endogenous pain control system makes it
feasible to erect a neurogenic hypothesis without completely
excluding some aspects of the humoral theory.
Because migraine is a familial disorder, there may well be
hereditary anomaly of monoaminergic transmission, that copes
well enough under normal circumstances. This mode of
transmission is vulnerable to sudden changes in the internal
or external environment to emotional stress, or to overload of
afferent systems by excessive glare, noise, smells, or other
stimuli. All of these factors are known to impinge on the
brain stem monoamine nuclei that project diffusely to the
cerebral cortex.
If monoaminergic systems were genetically unstable in subjects
prone to migraine, trigger factors could induce a phase of
excessive neuronal discharge followed by a state of monoamine
depletion. Finally, in a state of monoamine depletion, the
pain gate would be opened, giving rise to spontaneous pain in
the head and neck. The conclusion that central monoamine
systems play a central role in the pathophysiology of migraine
is difficult to escape.
Thus the physiologic and biochemical observations of patients
during migraine attacks led to the accumulation of a lot of
data awaiting synthesis. The common ground of the various
hypotheses for the mechanism of migraine is the involvement of
monoamines, neurotransmitters, centrally, and the humoral
agents(serotonin and adrenaline) peripherally. This is
supported by pharmacological evidence from the results of
treatment. Most effective interval therapy for migraine alters
the availability or action of serotonin (methysergide,
pizotifen), noradrenaline (beta-blocking agents), or both
monoamines (amitriptyline, monoamine oxidase inhibitors).
Other agents that act directly on vascular smooth muscle, such
as the calcium-entry blocking agents, may diminish
vasoconstriction, whether produced by humoral agents or by
intrinsic monoamine pathways from brain stem to cortex.
Non-steroid anti-inflammatory agents presumably suppress the
sterile inflammatory responses in vessel walls.
When is Headache a Warning of a More Serious Condition?
Like other types of pain, headaches can serve as warning
signals of more serious disorders.
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Migraine is
a risk factor for cerebral stroke, particularly in young
women. The symptoms and lesions of migrainous stroke
suggest the involvement of a mechanism similar to that of
migrainous aura, although the infarction process is of
greater intensity and lasts longer. Migrainous stroke
should be considered an evolutionary complication of aura.
Thus, the best treatment consists of adequate control of
migraine attacks with the reduction of frequency,
intensity and duration. The avoidance of migraine drugs
with marked vasoconstrictive action, and the removal of
other vascular risk factors (smoking and oral
contraceptives) are additional measures for the prevention
of migrainous stroke (18).
In addition to vasoconstriction, activation of clotting
factors plays a role in the pathophysiologic mechanism of
migraine-related stroke. However cerebro- and
cardiovascular evaluation is important in patients with
suspected migrainous stroke to exclude the diagnosis of
paradoxical cardioembolic stroke through a patent foramen
ovale (19). |
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Familial
hemiplegic migraine (FHM) is an autosomal dominant
condition. Attacks start in childhood, adolescence, or
early adulthood. They invariably include a unilateral
weakness lasting 30 to 60 minutes and almost always
associated with visual, sensory, or speech disturbances.
They are occasionally very severe with a dense hemiplegia,
confusion, coma or fever, but they always completely
recover. Brain neuroimaging is normal. In 20% of the
families, migraine is associated with permanent
neurological signs, mainly nystagmus and cerebellar ataxia
(20). |
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Migranous
infarction is reported due to severe diffuse intracranial
major arterial vasospasm that can be demonstrated by
arteriogram. Migranous infarction is represented by
recurrent episodes of migraine with aura, that progress to
develop a continuous intractable headache during the
course of which cortical blindness and quadriparesis
occurs due to extensive and bilateral hemispheric cerebral
infarction (21). |
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Brain
hemorrhage: The connection between brain hemorrhage and
migraine has been studied. It has been postulated that the
brain hemorrhage might be related to vascular lesion
brought about by ischemia secondary to vasospasm (22). |
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Intracranial
vascular malformations (IVM):Migraine is sometimes the
presenting feature of patients with intracranial vascular
malformations (IVM). A high prevalence of migraine type
headaches and a strong positive correlation between the
site of AVM and side of the pain was found (23). Migraine
could be the only complaint in patients affected by an
intrasellar aneurysm (24). |
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Migraine and
migraine-like headaches are sometimes associated with
acquired types of carotid artery stenosis or occlusion
(25). |
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Occipital
lobe tumor can be presented clinically as migraine with
typical aura (26). |
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Migraine
with aura has been reported as the presenting sign of
acute promyelocytic leukemia and disseminated
intravascular coagulation. This may support theories of
platelet serotonin involvement in the pathogenesis of
migraine (27). |
Danger signals that should alert the
physician to consider a potentially sinister cause:
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Sudden onset
of a new, severe headache-"the worst headache
ever" |
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A
progressive headache course. |
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Onset of
headache with exertion |
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Onset of
headache during or after middle age. |
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Headache
associated with a decreased level of consciousness. |
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Headache
associated with meningeal signs. |
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Headache
associated with abnormal physical signs including fever. |
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Failure of
headache to "fit" a benign profile. |
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Headache in
a patient with a systemic malignant disease, infection or
immunocompromised state. |
Clinical features that suggest the benign
nature of a migraine attack.
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Precipitation
by menstruation |
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Amelioration
with sleep. |
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Amelioration
during pregnancy |
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Appearance
after sustained exertion. |
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Triggers
such as alcohol, odors, foods, or changes in the
weather. |
Trigger Factors of
Migraine
Migraine attacks or other headaches are often triggered
(rather than caused) by one or more of the following factors:
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Stress is
the most frequently cited precipitant in migraine (28).
Patients most commonly recognize stress. Migraine brought
on by stressful situations and events. The onset of
attacks is usually during the period of calm immediately
after such moments of stress (29). |
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Odontogenic
pathogenic factors (dental problem), good diagnostic
examination in the field of tooth-, jaw- and mouth
medicine should be conducted in every migraine patient,
even in "typical" migraine patients. When
indicated, operations should be done (30). |
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Weather
changes e.g. Chinook weather conditions in the Calgary.
Older migraine sufferers appear particularly vulnerable to
this effect (31). |
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Cheese,chocolate,
red wine and beer sensitivity: it is believed that these
foods and several others contain vasoactive amines, such
as tyramine, which constrict arteries, the first step of
migraine process. Others believe that foods cause
headaches by setting off an allergic reaction in
susceptible people. Food-triggered migraine usually occurs
soon after eating (32). |
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Gastrointestinal
inflammation: Some of the children suffering from migraine
with or without aura have been found to have oesophygitis,
gastritis of corpus, antral gastritis or duodenitis. It is
postulated that there is a gastrointestinal origin of
these patients' complaints. findings provide evidence that
recurrent abdominal pain is an early expression of
migraine and strongly support a causal link between
recurrent abdominal pain and migraine(33). |
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Female sex
hormones fluctuatations: these fluctuations may trigger,
intensify, or alleviate migraine. Pharmacological
management of migraine in pregnant women must be
conservative because of the risks of injury and dependence
to the fetus and newborn (34). Motilium and Voltaren have
been successfully used for controlling vascular headache
developing as a side effect of contraceptive tablets. In
case of migraine associated with dysmenorrhoea and/or
premenstrual tension the management with triphasic hormone
proved to be of therapeutic value (35). |
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Minor trauma
to the head or whiplash neck injury: ("post-traumatic
migraine"-PTM). " The neurologic literature has
placed excessive emphasis on compensation neurosis and
psychological factors in the etiology of chronic headaches
after minor trauma. Physicians must be aware of PTM, as it
is both common and treatable (36). |
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Low back
pain: it has been found that in many patients, headache
was found to have begun or exacerbated markedly after
onset of low back pain. Potential mechanisms for
explaining the high prevalence of migraine following low
back pain, include increased muscle tension, psychosocial
factors, and analgesic overuse(37). |
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Migraine and
the eating disorders, particularly bulimia nervosa:
Bulimics appear to be more sensitive to the induction of
severe migrainous headaches than normal controls following
challenge with the 5-HT agonist (38). |
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Nitric oxide
(NO): it may play a key role in migraine and other
vascular headaches since glyceryl trinitrate (a donor of
NO) and histamine (which probably activates endothelial NO
formation) both cause a pulsating dose-dependent headache
with several migrainous characteristics. At relatively
high doses of glyceryl trinitrate, migraine sufferers
develop stronger and more migraine-like headaches and more
pronounced cerebral arterial dilatation than normal
controls (39). |
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A Common
denominator, namely, high levels of blood lipids and free
fatty acids are underlying factor in the development of
migraine headaches. Biological states that may cause
increases in free fatty acids and blood lipids include:
high dietary fat intake, obesity, insulin resistance,
vigorous exercise, hunger, consumption of alcohol, coffee,
and other caffeinated beverages, oral contraceptives,
smoking, and stress trigger migraine attack. Elevated
blood lipids and free fatty acids are associated with
increased platelet aggregability, decreased serotonin, and
heightened prostaglandin levels. These changes lead to the
vasodilatation that precedes migraine headache (40). |
UNDERSTANDING THE
PATHOPHYSIOLOGY OF MIGRAINE ASSISTS IN TREATMENT:
It is useful to conceptualize the patient with migraine as
having an inherited susceptibility to headache with altered
migrainous threshold. The expression of an altered migrainous
threshold in headache-prone persons may depend on the balance
between inhibitory and excitatory neurocircuits that are
influenced by a complex interplay of exogenous and endogenous
factors.
The best preventive strategy recognizes the multifactorial
nature of migraine and attempts to increase the migrainous
threshold through both pharmacological and non-pharmacological
interventions.
The serotonergic system:
It consists of the brain stem, with its descending and
ascending circuitry, including the ascending pain-modulating
projections from the midbrain raphe nuclei
The neural activity within this serotonergic system is an
important precursor to migraine.
Serotonin (5-hydroxytryptamine [5-HT])
It is a biogenic amine that is widely distributed throughout
the body. It is considered the serotonergic brain stem
generator. Any changes of serotonin can alter cranial
circulation and trigger a vascular phase. This neurovascular
reaction not only produces constriction or dilation of
intracranial and extracranial arteries but also activates the
nociceptive trigeminal vascular system. Neural connections
exist between the cerebral blood vessels and the trigeminal
nerve. Stimulation of the trigeminal sensory C fibers by any
of the triggering factors releases vasoactive neuropeptides.
These vasoactive neuropeptides include, substrate P and
calcitonin gene-related polypeptide and neurokinin A, an
outcome that results in a neurogenic or sterile inflammation,
which is blocked by 5-HT sub 1 receptor agonists such as
sumatriptan or dihydroergotamine (DHE ).
Seven classes of serotonin receptors have been identified.
Symptomatic agents are believed to act as agonists at the 5-HT
sub 1 receptor site. They act either peripherally or
centrally.
Prophylactic agents act as antagonists at the 5-HT sub 2
receptor site. They act centrally by "stabilizing" the
serotonergic system.
ASSESSMENT OF THE PATIENT WITH MIGRAINE
A detailed history is of paramount importance for an accurate
diagnosis
of migraine. The physician should ask why the patient is
seeking medical attention. The history should include the
following factors:
| • |
|
Age at
onset. |
| • |
|
Site of
pain. |
| • |
|
Frequency
and duration of pain. |
| • |
|
Character,
intensity and mode of onset of headache. |
| • |
|
Time between
onset to peak pain. |
| • |
|
Associated
neurologic, ophthalmologic, autonomic or systemic
symptoms. |
| • |
|
Sequence of
symptoms. |
| • |
|
Aggravating
or precipitating factors. |
| • |
|
Ameliorating
factors. |
| • |
|
Prior and
current medication use including dose, dosage schedule,
and efficacy. |
| • |
|
Caffeine
intake. |
| • |
|
History of
head trauma. |
| • |
|
Results of
prior neuroimaging studies. |
| • |
|
Family
history of similar diseases. |
| • |
|
A diary can
be helpful for documentation of headache frequency,
intensity,
compliance, and response to treatment. In addition, a
diary may disclose patterns related to lifestyle, diet,
menses, or medication overuse. |
Laboratory
investigation
Patients with typical migraine:
Neuroimaging or laboratory studies are unnecessary in the
routine diagnosis of typical migraine; however, it is
sometimes important to obtain an electrocardiogram and
baseline laboratory studies such as a hemogram and a chemistry
profile before initiation of therapy to ensure the safety of
intervention.
Patient with either a new onset of headache or a change in
a previously stable headache profile after 50 years of age:
Erythrocyte sedimentation rate, Cranial neuroimaging, high
quality enhanced computed tomography. In the case of a
suspected posterior fossa lesion in patients with a
progressive headache syndrome, papilledema, or abnormal
findings on neurologic examination, magnetic resonance imaging
should be done. If subarachnoid hemorrhage is suspected, then
examination of the cerebrospinal fluid with measurement of the
opening pressure is indicated after an appropriate imaging
study has excluded contraindication to lumbar puncture. In
cases of suspected bacterial meningitis, neuroimaging studies
do not need to be performed before a lumbar puncture in the
absence of papilledema and focal neurologic findings. Cerebral
angiography is indicated in cases of suspected central nervous
system vasculitis, arterial dissection, cerebral aneurysm, or
arteriovenous malformation.
PHARMACOLOGIC TREATMENT OF MIGRAINE
(41).
Effective management of migraine includes establishing
realistic expectations, patient reassurance, and education.
The choice of medication (abortive, symptomatic) for an acute
attack depends on such factors as:
| • |
|
The severity
of the attack. |
| • |
|
The presence
or absence of vomiting |
| • |
|
The time of
onset to peak pain. |
| • |
|
The rate of
bioavailability of the drug. |
| • |
|
The comorbid
medical conditions, and side-effect profile. |
Effective agents for acute attacks:
| • |
|
Simple or
combination analgesics. |
| • |
|
Non-esteroidal
anti-inflammatory drugs. |
| • |
|
Ergot
derivatives. |
| • |
|
Selective
serotonin agonists. |
Preventive (prophylactic, interval) medication
depends primarily on comorbid medical conditions and
side-effect profile.
Preventive agents:
| • |
|
Beta-adrenergic
blockers. |
| • |
|
Calcium
channel blockers. |
| • |
|
Tricyclic
antidepressants,. |
| • |
|
Anticonvulsant
medications. |
| • |
|
Serotonin
antagonists. |
It is recommended to explain to the patients
that they were born with a sensitive neurovascular system that
overreacts to internal changes or external stimuli and that
the condition can probably be controlled with
non-pharmacological and appropriate pharmacological treatment.
Patients are more likely to be active participants in their
treatment if they have a better understanding of their
condition. Patients may be referred to the Migraine
Association of Canada for information and support and may
benefit from referral to local self-help groups.
It is important to avoid analgesic overuse as it causes
rebound headache. Symptomatic medications, whether prescribed
or over-the-counter, when taken on a daily or almost daily
basis can result in a chronic daily headache syndrome that can
be refractory to treatment. An under-appreciated point is that
excessive use of symptomatic medications on a daily basis may
render prophylactic and symptomatic medications ineffective.
Symptomatic Therapy.
Symptomatic therapy is the mainstay of migraine management.
Effective treatment of the acute migraine attack should
terminate or decrease the symptoms of the attack.
· Simple Analgesics. It is recommended to use of ASA and
acetaminophen as the treatment of choice for mild to moderate
migraine attacks. Enteric-coated ASA , should not be used for
migraine because of delayed onset of action. Effervescent
preparations are more effective due to more rapid absorption
Combination Analgesics.
Two frequently used combination drugs effective in the
treatment of mild to moderate migraine attacks contain either
isometheptene with acetaminophen and dichloralphenazone or ASA
and acetaminophen with butalbital and caffeine. Both
combinations can cause a medication-induced or analgesic
rebound headache if used frequently. Therefore, we limit use
of these agents to no more than 2 days per week.
Nonsteroidal Anti-Inflammatory Drugs
NSAIDs is considered the first-line therapy for mild to
moderate migraine attacks. Selected examples include naproxen
sodium, ibuprofen, ketorolac, and indomethacin, NSAIDs are
contraindicated in patients with active ulcer disease.
Potential side effects include nausea, abdominal pain,
diarrhea, light-headedness, somnolence, and fluid retention,
as well as hepatic toxicity and nephrotoxicity.
Ergot Derivatives
Ergotamine Tartrate is effective symptomatic treatment of
moderate to severe migraine attacks that fail to respond to
simple or combination analgesics. Although both oral and
suppository dosing are available, plasma levels are 20 times
higher with rectal administration. A crucial and often
neglected point is that a sub-nauseating dose must be used.
Such a dose can range from one-quarter to a whole ergotamine
tartrate suppository.
Ergotamine tartrate is contraindicated in the following
conditions: women considering pregnancy and during pregnancy;
sepsis; inadequately controlled hypertension; cerebral,
coronary, and peripheral vascular disease; as well as hepatic
and renal insufficiency. Major side effects include abdominal
cramps, paresthesias, and nausea. The development of chest
tightness after use of ergotamine tartrate is a cause for
concern and necessitates discontinuation of use of the
medication and obtainment of an appropriate medical referral.
Patients should limit their use of ergotamine tartrate to no
more than 2 days per week and to take no more than 10 mg per
week. Overuse can produce ergotism and chronic daily
headaches.
Dihydroergotamine
Unlike ergotamine tartrate, DHE minimally constricts
peripheral arteries yet is a potent venoconstrictor. Unlike
ergotamine, DHE does not result in physical dependence. As
with ergotamine tartrate, the subnauseating dose must be
determined. Contraindications to the use of DHE are similar to
those for ergotamine tartrate.
Sumatriptan
Sumatriptan, a selective 5-HT sub 1 receptor agonist, has been
approved for treatment of acute migraine. Headaches recur in
up to 40% of patients probably because of the relative short
half-life of 2 hours. Sumatriptan administered subcutaneously
has a rapid onset of action, with statistically significant
relief being obtained in 10 minutes. Sumatriptan remains
efficacious even if given well into the headache phase. Its
beneficial effects on associated gastrointestinal symptoms
eliminate the need for coadministration of an antiemetic.
sumatriptan administered at the onset of a migraine aura has
no benefit. Oral sumatriptan therapy, which was recently
approved by the FDA, is similarly effective but has a slower
onset of action.
Sumatriptan is contraindicated in patients with inadequately
controlled hypertension, ischemic heart disease, Prinzmetal's
angina, and complicated migraine including vertebrobasilar
migraine, as well as in pregnant patients. Side effects of
subcutaneous sumatriptan therapy include discomfort at the
injection site, diffuse burning, tingling, and, occasionally,
neck or chest pain (or both). postmenopausal women, men older
than age 40 years, and patients with vascular risk factors
such as hypertension, hypercholesterolemia, obesity, diabetes,
smoking, and a strong family history of vascular disease
without a prior assessment for unrecognized coronary artery
disease (CAD).
Phenothiazines
Several controlled studies have demonstrated the efficacy of
intravenous chlorpromazine and prochlorperazine therapy.
However care must be taken to ensure adequate hydration before
use of intravenous chlorpromazine therapy. DHE and
prochlorperazine are miscible and can be combined in a single
syringe.
Corticosteroids
Prednisone, hydrocortisone, or methylprednisolone can be
considered for prolonged migraine attacks that are refractory
to the more standard treatment options. 3- to 5-day course of
outpatient oral corticosteroid therapy is sometimes used for
particularly refractory migraine attacks. Parentally
administered corticosteroids are useful for terminating a
severe, prolonged migraine attack when there are
contraindications to ergot preparations or when ergot
preparations have failed to provide relief.
Repeated use of corticosteroid is contraindicated as it causes
hormonal implance, cushing's disease, osteoporosis, diabetes
hypertension and lower the immune response to infections.
Narcotic Analgesics
Although meperidine is often used as an abortive agent in many
emergency departments, clinical trials to support widespread
use of this narcotic agent are lacking.
Prophylactic Therapy
Criteria for selecting patients for prophylactic
treatment
| • |
|
Attacks that
occur more than 2 to 3 times a month. |
| • |
|
Attacks that
last more than 48 hours. |
| • |
|
Attacks that
are severe. |
| • |
|
If the
patient is unable psychologically to cope with the
attacks. |
| • |
|
Treatment of
an acute attack provides inadequate relief or therapy
produces serious side effects |
| • |
|
Attacks
occur after prolonged aura.
Several additional factors must be considered before
prophylactic treatment can be initiated. |
Because of the potential teratogenic effect of
the prophylactic agents, women of childbearing age should be
using a reliable type of birth control. Prophylactic therapy
should be considered in patients taking excessive amounts of
symptomatic medications, which lead to rebound headaches.
Several pitfalls have been identified in migraine prophylaxis.
The dose may be inadequate, either insufficient or
excessive--it is prudent to "start low and go slow." The trial
regimen of treatment may be inadequate. The minimal time
interval for migraine prophylaxis before a beneficial effect
is noted is generally 1 to 2 months, especially when calcium
channel blockers are being used.
Although elimination of migraine is a worthy therapeutic goal,
in actuality, medications for Prophylaxis are seldom more than
55 to 65% effective. The medications used include
beta-blockers, calcium channel blockers, tricyclic
anti-depressants, anticonvulsants, serotonin antagonists,
NSAIDs, and MAO inhibitors.
Beta-Adrenergic Blocking Agents.
Beta-Blockers remain the treatment of choice for prophylaxis
of migraine, especially if the patient has comorbid
hypertension or anxiety. Examples of beta-blockers include
propranolol, nadolol, atenolol, timolol, and metoprolol.
Use of beta-blockers should never be discontinued abruptly.
Contraindications include asthma, insulin-dependent diabetes
mellitus, heart failure, heart block, pregnancy, and Raynaud's
phenomenon. Side effects, including lethargy, depression,
impotence, and hair loss, limit use of beta-blockers in many
people.
Calcium Channel Blockers.
Although calcium channel blockers are considered by some
investigators as first-line therapy for migraine prophylaxis,
the evidence in support of their efficacy is underwhelming.
Some investigators have suggested that verapamil has a
marginal benefit in decreasing the frequency of migraine
attacks. Several trials have used nifedipine and nimodipine in
the treatment of migraine. Nifedipine often causes a dull
persistent headache, and nimodipine is approved only for use
in subarachnoid hemorrhage and is too expensive to be used as
a long-term agent. Contraindications include hypotension,
heart block, sick sinus syndrome, and atrial fibrillation and
flutter. Constipation can be a troublesome side effect.
Tricyclic Antidepressants.
Amitriptyline is useful for migraine prophylaxis, particularly
in patients with coexisting depression, tension headaches, or
insomnia. Nortriptyline is as efficacious as amitriptyline,
but it has not been formally studied. Contraindications
include glaucoma, urinary retention, and cardiovascular
disease, particularly ventricular conduction abnormalities.
Anticonvulsants
Divalproex sodium has been shown to be an effective
prophylactic agent for migraine in several double blind,
placebo-controlled studies. This agent can be considered
first-line therapy for patients with coexisting seizures,
mania, or anxiety. Idiosyncratic reactions can include
hepatitis or pancreatitis.; clinical monitoring is thought to
be the best method for long-term management.
Serotonin Antagonists
Methysergide, a semisynthetic ergot, is effective in
preventing migraine attacks. Contraindications include CAD,
gastritis, uncontrolled hypertension, connective tissue
disease, and pregnancy. The major concern of methysergide is
the side-effect profile, which includes potential
idiosyncratic fibrotic complications. If the patient's
symptoms are relieved substantially, use of methysergide can
be slowly tapered after approximately 4 months. The
Physicians' Desk Reference recommends a medication-free
interval of 3 to 4 weeks after 6 months of continuous
treatment. For patients who receive methysergide for 6 months
or longer, periodic monitoring should include auscultation of
the heart, chest roentgenography, computed tomography or
magnetic resonance imaging of the abdomen, and urinalysis. As
with all medications, methysergide should be prescribed with
complete knowledge of the side-effect profile.
Nonsteroidal Anti-Inflammatory
Drugs.
Although NSAIDs can be used for migraine prophylaxis,
potential gastrointestinal and renal complications limit its
recommendation to short-term use. It is important to monitor
the serum creatinine.
Monoamine Oxidase Inhibitors
MAO inhibitors have been found to be effective in patients
with migraine headaches refractory to more standard treatment.
Before initiation of phenelzine, a dietary consultation is
advised. Patients must be given a list of medications and
foods that they should avoid, including over-the-counter
medications, particularly nasal decongestants.
NONPHARMACOLOGIC MANAGEMENT OF
MIGRAINE(42)
Augmentation of the use of non-pharmacological therapies for
the acute and prophylactic management of migraine is likely to
lead to substantial benefits in both human and economic terms.
Both the avoidance of migraine trigger factors and the use of
non-pharmacological therapies have a part to play in overall
migraine management.
Many of the non-pharmacological therapies are based on the
theoretic concept of migraine as resulting from neurochemical
instability within the brain. These approaches, which are
often "biobehaviouristic," may be complementary or adjunctive
to pharmacological treatment or may provide an alternative to
it.
Patient education
Patient education refers to "the information provided by
health professionals to headache patients. Patient education
is a necessary component of any treatment plan, and it is
recommended that it include the following items:
| • |
|
The
diagnosis of migraine should be given clearly and
confidently after the appropriate history-taking and
clinical examination and, when necessary, after
investigations have been completed. |
| • |
|
Patients
should be reassured that they do not have a serious
underlying cause for the headaches, such as a brain
tumor. |
Acute
non-pharmacological treatment
Most of the non-pharmacological measures found to be effective
in alleviating an acute migraine headache.
| • |
|
The
application of cold or pressure to the head has been
assessed as valuable. |
| • |
|
Reduction of
activity and of sensory input in a quiet or dark
environment and attempts to sleep. |
| • |
|
Relaxation
therapy, hypnosis, transcutaneous electrical stimulation,
acupuncture, and occipital or supraorbital nerve blockade
have also been used in the acute situation. |
BIOBEHAVIOURAL MEASURES
Biofeedback
Biofeedback refers to the use of monitoring instruments to
detect, amplify and display internal physiologic processes
on-line, so that the patient may learn to alter these
processes at will. Various types of biofeedback have been used
successfully as prophylaxis for migraine.
A report denying the value of biofeedback has also been
published, (36) and it is not possible to predict which
patients are most likely to benefit. The effect of combining
biofeedback with pharmacological therapy has seldom been
studied. Biofeedback requires a substantial time commitment on
the part of the patient, which may limit its use.
Relaxation therapy
Biobehavioural approach to migraine comprising relaxation
techniques (including progressive muscular relaxation,
breathing exercises or directed imagery) may or may not reduce
the frequency of episodes. Meta-analysis suggests that
relaxation is as effective as biofeedback. Where a treatment
effect has been reported, it may be enhanced by the addition
of prophylactic agents such as beta-blocking drugs. The usual
goal of relaxation therapy is the development of long-term
prophylaxis rather than the reduction of pain during an acute
attack. However, a few patients can abort a slowly evolving
migraine using these techniques.
Cognitive-behavioural therapy
Cognitive-behavioural therapy (CBT) is designed to help
patients identify and modify maladaptive responses that may
trigger or aggravate a migraine headache. The role of
emotional reactivity as a trigger for migraine is considered
to be pertinent in many patients, who may indulge in
self-blame, hopelessness and catastrophic thinking. CBT is
based on the principle that anxiety and distress are
aggravators of an evolving migraine headache; it attempts to
introduce a more adaptive approach as well as to help develop
a specific action plan. Stress-management training is often
part of this approach. CBT is usually combined with other
behavioural therapies but has been shown to be effective on
its own Individual therapist, group and self-help programs
have been used, with variable effects. However, as with other
behavioural therapies, such factors as availability, cost,
patient acceptance and the time commitment required may
restrict their use.
Psychotherapy
It is suggested that psychiatric referral of patients with
migraine is indicated solely for the presence of a coexistent
psychiatric disorder. However, referral to a psychologist to
improve stress management may be appropriate in selected
cases. The use of psychosocial interventions appears to be of
modest value Psychiatric referral of patients with migraine is
not indicated except in the presence of a coexistent
psychiatric disorder.
Hypnosis
Hypnosis may reduce distressing sensory input as it does in
other pain disorders and may have a placebo effect. It was
more effective than prochlorperazine in one randomized
controlled trial, and a meta-analysis of largely uncontrolled
studies also suggested benefit when hypnosis was combined with
CBT. However hypnosis may have a limited role in the
management of migraine in a small subgroup of patients who are
both willing and suitable subjects.
Physical measures
Complementary or alternative therapies may be described as
interventions that lack either a valid scientific basis or
adequate documentation of their effectiveness in the treatment
of specific conditions. Chiropractic, osteopathy and
acupuncture have been used in the management of migraine but
have rarely been subjected to trial, and evidence for the
superiority of any one form of cervical manipulation is
lacking. However it has been assumed that chiropractic
manipulations reduced migraine frequency and severity while
aerobic training may reduce the number but not the severity of
migraine headaches.
The value and cost-effectiveness of physiotherapy, osteopathy
and chiropractic in the management of migraine have not yet
been determined. It is therefore inappropriate for a physician
to refer patients for such treatments, but patients who are
strongly motivated to seek such help need not be dissuaded as
long as they are made aware of the uncertain benefits so far
recorded.
Transcutaneous electrical stimulation
and acupuncture
Transcutaneous electrical stimulation and have been claimed in
small series to provide some relief from migraine. Patients
who enquire about transcutaneous electrical stimulation and
acupuncture should be made aware of the lack of firm evidence
as to the benefits and cost-effectiveness of these treatments
in the management of migraine
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MIGRACELL
Migraine and its accompanying symptoms, complications, warning
signs and mechanisms have been extensively studied before
designing MIGRACELL. The scientific facts about the herbal
ingredients of this remedy have been studied very carefully,
with evidence of risks and benefits being made available to
consumers.
The MIGRACELL cream is composed of completely natural
ingredients that act synergistically. It is applied to the
site of pain and nasal mucus membrane. It has the ability to
penetrate the skin, the mucous membrane and the fine capillary
walls to blood circulation to exert abortive and prophylactic
effects in migraines and headaches without side effects.
THE MECHANISMS OF MIGRACELL ACTION
| • |
|
Regulates
the altered immune response common with migraines, to
activate the brain opiate system and control the pain. |
| • |
|
Exhibits
sedative and anxiolytic action. |
| • |
|
Inhibits the
contractile response of the vascular smooth muscles,
relieves the vasospasm and improves the brain circulation
that is always diminished during migraine attacks. |
| • |
|
Stops the
inflammatory response around the neurovascular system of
the brain that is responsible for the migraine pain,
through its anti-inflammatory action. |
| • |
|
Inhibits
platelet aggregation that might cause cerebral occlusion
and
neurological complications. |
| • |
|
Inhibits the
release of serotonin and histamine |
| • |
|
Improves the
mitochondrial energy metabolism which plays an important
role in migraine pathogenesis. |
| • |
|
Dampens
neuronal hyperexcitation, increases tolerance to focal
hypoxia, stabilizes platelets and lessens sympathetic
outflow. |
| • |
|
Inhibits
arachidonic acid (eicosanoid) metabolism. |
ACTIVE INGREDIENTS
| • |
|
Feverfew,
Tanacetum Parthenium. |
| • |
|
Balm,
Melissa officinalis, Labiatae |
| • |
|
Chamomile,
Matricaria recutita, compositae. |
| • |
|
Jamaican
Dogwood, Piscidia erythrina, Leguminosae. |
| • |
|
Linden,
Tilia tomentosa Moench, Tiliaceae. |
| • |
|
Salmon
Calcitonin. |
| • |
|
Magnesium. |
| • |
|
Taurine. |
| • |
|
Riboflavin. |
Feverfew, Tanacetum Parthenium compositae
Leaves or infusions of Feverfew, Tanacetum Parthenium, have
long been used as a folk remedy for fever, arthritis and
migraine. Feverfew contains a complex mixture of sesquiterpene
lactone and non-sesquiterpene lactone, which are inhibitors of
eicosanoid synthesis of high potency, and that these
biochemical actions may be relevant to the claimed therapeutic
actions of the herb (1).
Extracts of the herb Feverfew was found to inhibit human blood
platelet aggregation and secretion of serotonin (14C5-HT)
induced in-vitro by arachidonic acid and thromboxane and it
has been concluded that this may relate to the beneficial
effects of Feverfew in migraine (2).
A bioassay was developed to assess the in vitro activity of T.
Parthenium and its inhibitory effect on the release of
serotonin from bovine blood platelets. Inhibition of serotonin
release was shown to be significantly correlated with the
content of the germacranolide sesquiterpene lactone,
parthenolide (3). The structures of two series of
sesquiterpene lactones (the 'alpha'-series 11, 12 and 16 and
the 'beta'-series 15, 17 and 18) present in the herb Feverfew
have been revised in the light of both X-ray analysis and
chemical correlation. The activity of some of these
metabolites as well as of the major sesquiterpene lactone
present in Feverfew, as inhibitors of human blood platelet
function has been determined, The possible relevance of this
effect to migraine prophylaxis by Feverfew has been concluded
by some authors (4).
Studies showed that parthenolide may be a low-affinity
antagonist at 5HAT(histamine) receptors.
In vitro experimental studies showed that extracts of fresh
leaves of Feverfew caused dose- and time-dependent inhibition
of the contractile responses of the smooth vascular muscles.
This inhibitory effects was concluded to be due to
Parthenolide (6) and its effect on the contractile responses
of the smooth vascular muscles could be a factor in the
ability of Feverfew extract to reverse the cerebral vasospasm
that occurs in migraine attacks and sometimes leads to
cerebral ischemia.
Studies showed that the mean frequency of chromosomal
aberrations in the Feverfew user group was lower than that in
the non-user group both in terms of cells with breaks (2.13%
vs. 2.76%) and in terms of cells with all aberrations (4.34%
vs. 5.11%). This difference was small and not significant (7),
however, this observation merit further studies to see whether
the Feverfew has any effect on the chromosomal aberration
found in many migraine patients.
Systematic review was made to look at the evidence for or
against the clinical effectiveness of Feverfew in migraine
prevention. Two independent reviewers read all articles. Five
trials met the inclusion/exclusion criteria. The majority
favor Feverfew over placebo (8).
One of the clinical trials was to assess the effectiveness of
Feverfew as a prophylactic therapy for migraine; a
double-blind placebo controlled crossover trial was conducted
for a period of 4 months. Fifty-seven patients who attended an
outpatient pain clinic were selected at random and divided
into two groups. Both groups were treated with Feverfew in the
preliminary phase (phase 1), which lasted 2 months. In the
second and third phases, which continued for an additional 2
months, a double blind placebo-controlled crossover study was
conducted. The results showed that Feverfew caused a
significant reduction in pain intensity compared with the
placebo treatment. Moreover; a profound reduction was recorded
concerning the severity of the typical symptoms that are
usually linked to migraine attacks, such as vomiting, nausea,
sensitivity to noise and sensitivity to light. Transferring
the Feverfew-treated group to the placebo treatment resulted
in an augmentation of the pain intensity as well as an
increase in the severity of the linked symptoms. In contrast,
shifting the placebo group to Feverfew therapy resulted in a
reduction of pain intensity as well as the severity of the
linked symptoms (9).
Balm, Melissa officinalis, Labiatae
Rosmarinic acid (RA), a naturally occurring extract from
Melissa officinalis, inhibits several complement-dependent
inflammatory processes (11).
The sedative effects of Melissa officinalis extracts was
proved by quantitative EEG analysis and by self-assessment
(12)
It has been proved by experimental analysis that Melissa
officinalis, contained high concentrations of total ascorbic
acid (approximately equal to 300 mg/100 g FW) and relatively
high ascorbate oxidase activity (10.1-21.1 micro mol min-1 g
FW-1) (13). Besides acting as an important cofactor in the
modulation of the biosynthesis of catecholamine, ascorbic acid
(AA) has an active role in the post-translational modification
of neuropeptides. AA in modulates the secretion of
immunoreactive beta-endorphin (ir-beta EP) (14). As a result
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