By-Dr Sadaf Siddiqui
Headache is the most common complaint for which
people see neurologists and the seventh most common
reason they visit their primary care doctors.
Headache is the third most common cause of missed
work and it affects every area of a person’s life.
Hippocrates believed that headache could be triggered
by exercise or intercourse and migraine resulted from
vapors rising from the stomach to the head and that
vomiting could partially relieve the pain of headache.
The term migraine itself is derived from the Greek word
‘hemicrania’, introduced by Galen in approximately AD
Clearly, migraine was well known in the ancient world.
Migraine was distinguished from common headache by
Tissot in 1783.
The most widely used headache classification system
was developed in 1988 by the International Headache
Society (IHS), and revised in 2004.
With the IHS system,
Part 1 of the system classifies the primary headaches,
Part 2 classifies the secondary headaches, and
Part 3 of the system classifies the cranial neuralgias,
central and primary facial pains, and other headaches.
The primary headache disorders are those in which the
headache condition itself is the problem, and no
underlying or dangerous cause for it can be identified.
Secondary headaches are those due to an underlying
condition such as a tumor, infection or hemorrhage. The
secondary headaches are classified according to their
causes (e.g. vascular, psychiatric,etc.)
The ‘big three’ primary headache disorders,
• Migraine is the most common headache problem that
causes patients to seek medical help.
• Tension-type headache is the most common headache
disorder, but it is usually mild and self-limiting. It generally
prompts medical consultation only when chronic.
• Cluster headache is the most severe of the three
conditions, but it is uncommon
Migraine - Definition
“Migraine is a familial disorder characterized by recurrent
attacks of headache widely variable in intensity, frequency and
duration. Attacks are commonly unilateral and are usually
associated with anorexia, nausea and vomiting”
World Federation of Neurology
INTERNATIONAL HEADACHE SOCIETY (IHS)
Migraine without aura
Migraine with aura
Childhood periodic syndromes that are commonly
precursors of migraine
Complications of migraine
Migraine is one of the most burdensome of the primary
Epidemiologic data can be used to describe this burden
as well as its scope and distribution Understanding
sociodemographic, genetic, and environmental risk
factors for migraine helps identify groups at highest risk
for migraine and may provide clues to treatment
strategies or disease mechanisms.
THE EPIDEMIOLOGY OF MIGRAINE
The Incidence of Migraine
It is found that in females, the incidence of migraine with
aura peaked between ages 12 and 13 and migraine
without aura peaked between ages 14 and 17.
In males, migraine with aura peaked in incidence several
years earlier, around 5 years of age and the peak for
migraine without aura was between 10 and 11 years.
THE PREVALENCE OF MIGRAINE
Before puberty, migraine prevalence is higher in boys than in
Adolescence- incidence and prevalence increase more
rapidly in girls than in boys.
The American Migraine Prevention and Prevalence study
(AMPP) showed the prevalence of migraine was about 18% in
women and 6% in men.
overall prevalence of headache increases from preschool age
children to mid adolescence.
One year period prevalence of migraine by age and sex adjusted for
THE BURDENS OF MIGRAINE
The Burden of Migraine to the Individual
Migraine is a public health problem of enormous scope that
has an impact on both the individual sufferer and on society.
The AMPP, conducted in 2005, estimated that in migraine
attacks, most migraineurs reported severe impairment or the
need for bed rest (53.7%).
Over a 3-month period, 35.1% of the migraineurs had at least
1 day of activity restriction related to headache.
NEJM 2002; 346(4): 257-269; XI Congress of the IHS, 2004
The Burden of Migraine to the Family
A Canadian study reported that 90% of people with
migraine reported postponing their household work
because of headaches, 30% had canceled family and
social activities during their last migraine attack, and
two-thirds feared letting others down because of their
One half believed that, because of their migraine, they
were more likely to argue with their partners (50%) and
Both epilepsy and migraine can cause headache and
transient alterations of consciousness.
Prodromal migraine symptoms, such as fatigue and
irritability, may be part of comorbid depression.
The presence of comorbidity may provide clues to the
pathophysiology of migraine, Independent genetic or
environmental risk factors may produce a brain state
that gives rise to both migraine and a comorbid
Stress and anxiety
Sleep deprivation or excess
Vague premonitory symptoms that begin from 12 to 36
hours before the aura and headache
Craving or distaste for various foods
Duration – 15 to 20 min
Aura is a warning or signal before onset of headache.
Flashing of lights
Difficulty in focussing
Duration : 15-30 min
Headache is generally unilateral and is associated with
Duration is 4-72 hrs
Following headache, patient complains of
Some patients feel unusually fresh
Duration: Few hours or up to 2 days
Migraine has a strong genetic component.
Approximately 70% of migraine patients have a first-
degree relative with a history of migraine.
The risk of migraine is increased 4-fold in relatives of
people who have migraine with aura.
Kors EE, Haan J, Ferrari MD. Genetics of primary headaches. Curr Opin Neurol
The Hyperexcitable Brain
Migraine patients have a brain that is too excitable, a so-
Specific neurons in the brain—or nuclei—discharge too
easily, activating pathways that initiate the mechanism
of pain and associated symptoms, and resulting in the
migraine syndrome. The tendency to fire is what is
There are many hypotheses about what it is in neurons
that makes them hyperexcitable.
One possibility is that migraine nerve cells are too
sensitive to nitric oxide, a chemical messenger released
by some nerve cells to activate certain others
Another theory is that some patients with migraine have
too little magnesium in the brain.
Low magnesium may lead to nerves becoming
hyperexcitable. Low magnesium destabilizes nerves by
altering the ability to control the influx and efflux of
charged ions, resulting in nerve cells firing too easily
Calcium Channels and Familial Hemiplegic Migraine
The genetic basis for some patients with this very rare form
of migraine, familial hemiplegic migraine (FHM), has been
The mutant calcium channel does not open and close
properly and cannot regulate the amount of calcium coming
into the cell, so calcium influx and efflux regulation goes awry.
This in turn leads to neurons firing too easily. Because
abnormal calcium channels are a cause of FHM, blocking
them with a calcium channel blocker specifically treats this
form of migraine
In 1944, Leao proposed the theory of cortical spreading
depression (CSD) to explain the mechanism of migraine with
CSD is a well-defined wave of neuronal excitation in the
cortical gray matter that spreads from its site of origin at the
rate of 2-6 mm/min.
This cellular depolarization causes the primary cortical
phenomenon or aura phase; in turn, it activates trigeminal
fibers, causing the headache phase
The neurochemical basis of the CSD is the release of
potassium or the excitatory amino acid glutamate from neural
This release depolarizes the adjacent tissue, which, in turn,
releases more neurotransmitters, propagating the spreading
Functional MRI and other physiological studies of humans
with aura suggest that this is the cause aura is therefore be
neurological, not vascular..
The Migraine Generator
This is the area in the lower part of the brain (brain-
stem) in which nerve cells turned on at the beginning of
the migraine, remained on for the length of the migraine
and clicked off at the end of the migraine.
This center is known as the migraine generator.
The exact location for the generator may be the dorsal
raphe nucleus of the brainstem.
The migraine generator connects to nerve pathways that lead
to the meninges, coverings around the brain between brain
These pathways lead to other nerves that encircle and serve
blood vessels of the meninges.
When this occurs, blood vessels in the meninges dilate and
the neurons release inflammatory chemicals around the
vessels. The combination of meningeal blood vessel dilation
and inflammation is believed to be the cause of migraine
Migraine headache-how it is
It was believed that ischemia induced by intracranial
vasoconstriction is responsible for the aura of migraine and
that the subsequent rebound vasodilation and activation of
perivascular nociceptive nerves resulted in headache.
This theory was based on the following 3 observations:
Extracranial vessels become distended and pulsatile during a
Stimulation of intracranial vessels in an awake person
Vasoconstrictors (eg, ergots) improve the headache,
whereas vasodilators (eg, nitroglycerin) provoke an
Complex series of neural and vascular events initiates
migraine is primarily a neurogenic process with
secondary changes in cerebral perfusion.
Involves abnormal activation of trigeminocervical
Cutrer FM, Charles A. The neurogenic basis of migraine. Headache
The Trigeminovascular System
The connection between the migraine generator and the
nerves and blood vessels of the meninges is called the
To simplify: the migraine central generator clicks on the
switch, the trigeminovascular system is activated, the blood
vessels of the coverings of the brain dilate, and the meninges
The central generator is in the brain and the peripheral pain
mechanism in the meninges.
A primary dysfunction of brain stem pain and vascular
control centers elicits a cascade of secondary changes in
vascular regulation within pain-producing intracranial
structures that ultimately manifests in headache pain
and associated symptoms.
A synthesis of these views and observations forms the
neurovascular hypothesis of migraine.
This suggest that there are several key steps in the
generation of migraine pain:
(1)-Intracranial meningeal blood vessel dilation which activates
perivascular sensory trigeminal nerves
(2) Vasoactive neuropeptide release from activated trigeminal
These peptides can worsen and perpetuate any existing
vasodilation, setting up a vicious cycle that increases sensory
nerve activation and intensifies headache pain.
The peptides include substance P (increased vascular
permeability), neurokinin A (dilation and permeability
changes) and calcitonin gene-related peptide (CGRP; long-
(3) Pain impulses from activated peripheral sensory nerves are
relayed to second-order sensory neurons within the trigeminal
nucleus caudalis in the brain stem and upper cervical spinal cord
(C1 and C2, trigeminocervical complex).
(4) Headache pain signals ascend to the thalamus, via the
quintothalamic tract which decussates in the brain stem, and on
to higher cortical centers where migraine pain is registered and
Serotonin and migraine
The serotonin receptor (5-hydroxytryptamine [5-HT]) is
believed to be the most important receptor in the headache
Serotonin is a neurotransmitter that can both excite and
inhibit— and therein lies the story of how it controls
5-HT1 receptors are negative or inhibitory receptors; 5-HT2
receptors are positive or excitatory receptors.
When serotonin binds to the excitatory 5HT2 receptors
near the migraine central generator, it turns on the
Serotonin, activating the 5-HT1D receptor, may help get
rid of migraine pain by inhibiting CGRP release.
Therefore, when the serotonin binds to both 5-HT1B and
5-HT1D receptors, both mechanisms of migraine, blood
vessel dilation and inflammation, are turned off.
Burstein et al described the phenomenon of cutaneous
allodynia, in which secondary pain pathways of the
trigeminothalamic system become sensitized during a
This observation demonstrates that, along with the
previously described neurovascular events, sensitization
of central pathways in the brain mediates the pain of
1.Burstein R, Yarnitsky D, Goor-Aryeh I, Ransil BJ, Bajwa ZH. An association between
migraine and cutaneous allodynia. Ann Neurol
Some authors have proposed a dopaminergic basis for
dopaminergic hypersensitivity is present in patients with
Few symptoms of migraine headaches, such as nausea,
vomiting, yawning, irritability, hypotension, and hyperactivity,
can be attributed to relative dopaminergic stimulation.
Dopamine antagonists (eg, prochlorperazine) completely
relieve almost 75% of acute migraine attacks
1. Peroutka SJ. Dopamine and
Menstrual and Hormonal Aspects of Migraine
Migraine often begins—or increases dramatically—when a
woman enters puberty and generally improves after
This is due to the fact that the sex hormones estrogen and
progesterone have an effect on migraine.
The most distinctive form of menstrual migraine occurs just
after the onset of flow and appears to be due to the sudden
drop in estrogen that occurs around the menses.
Replacing estrogen reduces the occurrence of these migraine.
Establish a partnership with the patient
Promote patient education
Establish a treatment plan
• Nature and mechanism of the disorder
• Strategies for identifying and avoiding triggers
Acute treatment principle
Treat early in attack
Use correct dose and formulation
Use for a maximum of 2 to 3 days per week
Treat at least two different attacks with same medication
before determining efficacy.
If treatment ineffective
Use optimal dose
Change formulation/route of administration
Be sure there are no interfering medications or overuse
There are two strategies for initial therapy: step care and
use of medications in a sequential order, based on a
Therapy starts with the lowest level of treatment,
independent of the characteristics of the attack.
This approach to treatment is not necessarily based on the
individual needs of the patient.
treatment based on attack characteristics, including peak
intensity, time to peak intensity, associated symptoms,
It is also individually tailored to specific patient needs.
Stratified care takes into account patient preferences for
treatment and allows the patient to select medications
for each particular attack.
INCREASING EVIDENCE FOR TREATING
EARLY WHEN PAIN IS MILD
Retrospective studies (sumatriptan , zolmitriptan and
almotriptan) support higher pain-free rates when
treating while pain is mild
Retrospective analysis: triptans, ergotamine plus
caffeine, and aspirin plus metoclopramide, all provided
higher pain-free response. Triptans more effective and
Prospective rizatriptan study: effective at all levels of
pain but enhanced benefit if taken while pain is mild
Cady RK et al. Headache. 2000. Cady RK et al. Clin Ther. 2000.
Hu XH et al. Headache. 2002. Winner et al. Mayo Clin Proc. 2003
CONSIDERATIONS FOR TREATING
EARLY IN THE ATTACK
May prevent disability
May reduce headache recurrence and decrease number of
tablets used per attack
May prevent sensitization and allodynia
Treating early may lead to over treatment
To avoid overuse: limit use of acute treatment to no more
than 3 days per week
Triptan (serotonin 1B/1Dreceptor agonists)
Effective and safe
Appropriate initial choice in patients with moderate to
Routes-oral, subcutaneous and nasal
Drugs – sumatriptan-50-100mg tablet at onset , may
repeat after 2hour (max 200mg/d)
Rizatriptan –most efficacious, early onset of action,
5-10 mg tablet at onset may repeat after 2hr max
Naratriptan, almotriptan,frovatriptan, zolmitriptan
Triptans should not be used more than 3 days weekly to
avoid transformed migraine and medication overuse
Caution-avoid in patients of CAD
Paresthesia, jaw or neck tightness, warm/cold sensation
Ergot alkaloids and derivatives-nonselective 5-HT1
Ergotamine PO/PR (and caffeine combination) may be
considered in the treatment of selected patients with
moderate to severe migraine.
Dose 2mg PO, f/b 1-2mg every 30 min until attack is
aborted, no more than 6mg/day
Adverse effects-vasospasm, angina, tachycardia, numbness
of extremities, rebound headache, ergotism, gangrene etc
Dihydroergotamine- alpha adrenergic blocking agent
with a direct stimulating effect on smooth muscle of
peripheral and cranial blood vessels. It is a non selective
Route- iv or nasal
Dose- 1mg iv/im repeated 1 hrly , no more than 3 mg for
im and 2mg for iv
Nasal-1 spray 0.5mg in each nostril not more than 6
DHE nasal spray is effective for the treatment of acute
migraine attacks and should be considered for use in
patients with moderate to severe migraine
DHE IV plus antiemetics IV is an appropriate treatment
choice for patients with severe migraine
Oral antiemetics are an adjunct to treat nausea associated
with migraine .
Metoclopramide IM/IV is an adjunct and may be considered
as IV monotherapy for migraine pain relief
Prochlorperazine IV, IM, and PR may be a therapeutic choice
in the appropriate setting
5-HT3 antagonists may be considered as adjunct therapy to
control nausea in selected patients with migraine attacks
NSAIDs, nonopiate analgesics, and combination
Acetaminophen, alone, is not recommended for
NSAIDs (oral) and combination analgesics containing
caffeine are a reasonable first-line treatment choice for
mild to moderate migraine attacks or severe attacks that
have been responsive in the past to similar NSAIDs or
Butorphanol nasal spray is a treatment option for some
patients with migraine.
Butorphanol may be considered when other medications
cannot be used or as a rescue medication when
significant sedation would not jeopardize the patient
Isometheptene and isometheptene combination agents
may be a reasonable choice for patients with mild-to-
moderate headache .
Corticosteroids (dexamethasone or hydrocortisone) are a
treatment choice for rescue therapy for patients with
ACUTE MIGRAINE TREATMENT
IN URGENT CARE SETTING
Consider sumatriptan sc
Start an IV and hydrate
Start repetitive IV treatment
• Antiemetics plus DHE
• Ketorolac 30-60 mg IM
• Magnesium? Valproate?
WHEN IS PROPHYLAXIS INDICATED?
According to the US Headache Consortium Guidelines,
indications for preventive treatment include:
Patients who have very frequent headaches (more than
2 per week)
Attack duration is > 48 hours
Headache severity is extreme
Migraine attacks are accompanied by prolonged aura
Unacceptable adverse effects occur with acute migraine
Contraindication to acute treatment
Migraine substantially interferes with the patient’s daily
routine, despite acute treatment
Special circumstances such as hemiplegic migraine or
attacks with a risk of permanent neurologic injury
5 principal classes of drugs are used -:
Divalproex and valproic acid are among the first-line
agents in migraine prevention
The initial dose is usually from 250 mg daily, titrated up
to 1,500 mg.
Ramadan NM, Silberstein SD, Freitag FG, Gilbert TT, Frishberg BM, for the US Headache Consortium. Evidence-based
guidelines for migraine headache in the primary care setting: pharmacological management for prevention of migraine
Amitriptyline- 10-75mg at night
Selective serotonin reuptake inhibitors
Bupropion, mirtazepine, trazodone, venlafaxine
Tricylic antidepressants are another class of medication
considered as first-line treatment in migraine
Response is usually more rapid (within 4 weeks) than
Tertiary amines, such as amitriptyline, are more
effective than the secondary amines, such as
Couch JR, Hassanein RS. Amitriptyline in migraine prophylaxis. Arch Neurol
Evans RM. Managing migraine today (II): pharmacologic and nonpharmacologic treatment [JAMA Migraine
The scientific and clinical evidence supports β-blockers
as the drugs of choice for the prevention of migraines.
The most commonly used agent is propranolol
Noble SL, Moore KL. Drug treatment of migraine: part II. preventive therapy. Am Fam Physician 1997
Anxiety or panic attacks (specifically propranolol)
Calcium channel blockers
Calcium channel blockers are effective second-line
They are usually slower in onset than β-blockers, and an
initial increase in headache frequency may occur.
Daily dose range
Verapamil hydrochloride: 120 to 480 mg
Nifedipine: 30 to 90 mg
Diltiazem: 120 to 360 mg
Nimodipine: 60 to 120 mg
Aspirin ,Mefenamic acid,Ibuprofen,Naproxen/naproxen
The NSAID naproxen sodium has also been used for
In controlled clinical trials, naproxen sodium
demonstrated better efficacy than placebo and similar
efficacy to propranolol.
However, this agent should be reserved for short-term
use, such as for menstrual migraines
Two medications that have proved effective in
prophylaxis but are reserved for severe or refractory
cases are methysergide and phenelzine sulfate.
Methysergide is the fourth agent indicated and approved
for migraine prophylaxis by the FDA.
Phenelzine—a monoamine oxidase inhibitor should be
considered only in severe refractory cases, specifically
those that are compounded by tension headaches or
drugs with an uncertain or unproven role in migraine
The efficacy of fluoxetine hydrochloride has not been well
established in prophylaxis, but some experts already consider
it a viable alternative to tricyclic antidepressants.
Some evidence exists that riboflavin (vitamin B2) in high doses
(400 mg daily) has some effect in migraine prophylaxis.
Similarly, magnesium at doses of 400 to 600 mg daily may
also be of benefit, but there is less evidence for its efficacy
than that for riboflavin.
Schoenen J, Jacquy J, Lenaerts M. Effectiveness of high-dose riboflavin in migraine prophylaxis: a randomized
controlled trial. Neurology 1998
The United States Headache Consortium pointed out
that nonpharmacologic treatments might be particularly
well suited for patients who
1. Have a preference for nonpharmacologic interventions
2. Display a poor tolerance for specific pharmacologic
3. Exhibit medical contraindications for specific
4. Have insufficient or no response to pharmacologic
5. Are pregnant, are planning to become pregnant, or
6. Have a history of long-term, frequent, or excessive use
of analgesic or acute medications that can aggravate
headache problems (or lead to decreased
responsiveness to other pharmacotherapies)
7. Exhibit significant stress or deficient stress-coping
The FDA approved the Cerena Transcranial Magnetic
Stimulator (Cerena TMS), the first device to relieve pain
caused by migraine headache with aura.
Users hold the device with both hands to the back of the
head and press a button to release a pulse of magnetic
energy that stimulates the occipital cortex.
The recommended daily usage of the device is not to
exceed one treatment in 24 hours.
US Food and Drug Administration. FDA allows marketing of first device to relieve migraine headache pain
December 13, 2013.
Complementary and Alternative Treatments
A variety of other CAM techniques may be perceived to be of
benefit to patients.
Techniques that some patients use for headache relief include
Body work - Eg, chiropractic, massage, and craniosacral
Nutritional/herbal supplements - Eg, vitamins and herbs
Acupressure and acupuncture
BiofeedbackLinde K, Vickers A, Hondras M, ter Riet G, Thormählen J, Berman B, et al.
Systematic reviews of complementary therapies
Surgical therapy for migraine is highly controversial. In a study
of 60 patients, Dirnberger and Becker reported that
corrugator muscle resection produced total relief of migraine
in 28.3% of patients, essential improvement in 40%, and
minimal or no change in 31.7%. The more severe their
migraine, however, the less likely patients were to experience
In addition, 11 patients who had a very favorable short-term
response experienced a gradual return of their headaches to
preoperative intensity within about 4 weeks
Dirnberger F, Becker K. Surgical treatment of migraine headaches by corrugator muscle
resection. Plast Reconstr Surg. 2004
Novel Treatments and Future Drugs
Tonabersat is a novel benzopyran compound that markedly
reduces cortical spreading depression (CSD) and CSD-
associated events by inhibiting gap-junction communication
between neurons and satellite glial cells in the trigeminal
Durham PL, Garrett FG. Neurological mechanisms of migraine: potential of the
gap-junction modulator tonabersat in prevention of migraine. Cephalalgia. 2009
The pipeline of future compounds for the treatment of acute
migraine headaches also includes the following medications:
Transient receptor potential vanilloid type 1 antagonists
Prostaglandin E receptor 4 receptor antagonists
Serotonin 5HT1(F) receptor agonists
Nitric oxide synthase inhibitors
Blau jn. migraine: theories of pathogenesis. Lancet. 1992;339:1202-1207.
Ramadan nm, silberstein sd, freitag fg, gilbert tt, frishberg bm, for the us
headache consortium. evidence-based guidelines for migraine headache
in the primary care setting: pharmacological management for prevention
of migraine [am acad neurol web site]. april 25, 2000.
Migraine prophylaxis in adult patients, west j med. 2000 nov; 173(5): 341–
Atlas of migraine and other headaches second edition
Neurol clin 27 (2009),migraine and other primary headache
Understanding migraine and other headaches,stewart j tepper,md