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160 Chi Tim HUNG, Steven H.S. WONG
diseases, while the sudden onset of severe headache
or the sudden change in the character of headache
prompts for further investigation. e pattern of
pain is important to differentiate cluster headaches
from other headaches. Whereas trigeminal neuralgia
is episodic in nature with each attack lasting
minutes, organic headaches tend to be continuous
with acute exacerbations caused by exercise, change
in posture and the Valsalva manoeuvre.
Headache intensity that peaks rapidly is suspicious
of organic disease, except trigeminal neuralgia
and cluster headache. e region of the headache
is important. Different types of headaches have
their characteristic locations of pain (Table 10.03),
although there is a tremendous overlap between
different headache syndromes [107]. Typically
most headache syndromes are unilateral except
for tension-type headache. Localised pain around
anatomical structures raises the possibility of
pathology involving them. e broad division
of head and face pain helps to limit the number
of differential diagnoses one has to consider. e
quality of pain must be assessed. Vascular headaches
typically are throbbing in character. Neuralgia pains
are typically brief shock-like pains. e tension-type
headaches are dull aching in nature with occasional
exacerbations. Provoking and relieving factors of
Table 10.03 Comparison between three different primary headaches
Migraine Cluster headache
(episodic)
Tension-type
(episodic)
Sex
F>M M>F F>M
Age of onset
20–40 years, 25% before
10 years
Late 20s Any age
Site of pain
Retro-orbital,
frontotemporal, may
radiate to occiput and
neck
Area of trigeminal
innervation, periorbital
Bifrontal, bioccipital
Side of pain
Typically unilateral, can
be bilateral
Strictly unilateral Bilateral
Character of pain
throbbing Non-throbbing,
excruciating, penetrating
Dull, non-throbbing,
constriction-band like
Pain duration
4–72 hours 15 min to 3 hours 30 min to 7 days
Pain frequency
Single attacks with
periods of freedom
Daily or several times a
day during cluster period
No definite pattern, <15
days per month, <180
days per year
Time of headache
Waking hours Predilection for hours of
sleep
Later in day
Remissions
Shorter remissions Long remissions between
clusters
Aura or prodrome
Present in migraine with
aura (10–20%), mainly
visual aura
No No
Associated symptoms
Nausea, vomiting,
photophobia,
phonophobia
Ipsilateral lacrimation,
nasal stuffiness,
rhinorrhoea
Stress
Exacerbation
Physical activity No relation to activity No relation to activity
Abnormal signs
None during headache Ptosis, Miosis None
Family history
Positive in 50% Usually negative Absent
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Headache 161
the pain are important. ese factors like posture,
diurnal patterns and the Valsalva manoeuvre may
shed light onto the organic nature of the headache.
Precipitating factors like stress, fatigue or alcohol
points to tension-type headache as an aetiology.
Migraine on the other hand can be triggered by
food containing tyramine, nitrates or monosodium
glutamate, alcohol, menstruation, diet or sleep
habit changes. Alcohol and vasodilating substances
may also trigger cluster headaches. e premonitory
and associated symptoms are important for the
diagnosis of migraine and cluster headaches. Aura
refers to symptoms of cerebral neuronal dysfunction
presenting as ocular, auditory, olfactory, motor and
sensory symptoms. Associated symptoms to look
for include photophobia, nausea and vomiting,
sonophobia and aversion to strong odours. Cluster
headaches could be accompanied by autonomic
symptoms like lacrimation, rhinorrhoea, flushing
and Horner’s Syndrome. Other neurological
changes during the attack of headache could be
associated with organic diseases.
In the medical history, the presence of skin rash
suggestive of preceding herpes infection in the head
and face region must be sought. Familial history
of similar headache may be suggestive of migraine
[42, 81] or cluster headache [46, 82]. Interested
readers may refer to a review of the genetics of
migraine by Merikangas [67]. A history of trauma
is also important.
Physical examination
As with history taking, one must look for signs
suggestive of organic diseases in the physical
examination. A complete examination including
the psyche, head, face, oral cavity, cervical spine,
full neurological examination and other bodily
systems will be mandatory. e general appearance
gives some clues to the psychological make-up of a
patient, such as whether the patient is depressed,
anxious or detached. Skin is examined for scars,
local infection and possible tumours. Tender spots
may be felt over the face, occipital and neck regions;
they may reveal local pathology or trigger points
of the myofascial syndromes. e trigger areas for
trigeminal neuralgias may be evident during the
examination of the face. e temporal artery may
be tender to palpation. e oral cavity has to be
examined for dental and tongue disorders. e
temporo-mandibular joint needs to be assessed for
alignment, mobility and clicking. e neck has
to be examined for lymph nodes and the range of
movement of the cervical spine assessed to rule out
meningeal irritation or spine abnormalities.
A full neurological examination includes all the
cranial nerves, the sensory system, the motor system
and the reflexes. e fundoscopic examination is
also essential. Signs of autonomic dysfunction like
allodynia in the anterior triangle of the neck in
the presence of antecedent trauma is suggestive of
regional pain syndromes involving the face [106].
e upper limbs have to be examined for radicular
signs that would suggest cervical spine diseases.
Other body systems need to be examined to exclude
systemic diseases.
Investigations
e majority of primary disorders will not show
positive changes on laboratory testing. Laboratory
testing is therefore essential to rule out organic
diseases before diagnosing primary disorders.
Apart from simple blood tests, neuroimaging
like computed tomography (CT) and magnetic
resonance imaging (MRI) are increasingly used in
evaluation of headache patients. Neuroimaging for
migraine has been extensively studied. Evidence-
based guidelines are necessary to avoid performing
expensive tests with a great majority showing
negative findings. e presence of sinister clinical
features (Table 10.04) is a useful guide for choosing
these neuroimaging studies. Frishberg reviewed
available literature and concluded that in migraine
patients with neither physical signs nor abnormal
history, the routine use of neuroimaging is not
warranted [30]. Neuroimaging will be indicated
for patients with atypical headache patterns, a
history of seizures, or focal neurological signs or
symptoms. e Quality Standards Committee of
the American Academy of Neurology now adopts
this as a guideline [23, 77]. However, there is as yet
not enough evidence to make recommendations for
headache disorders not consistent with migraine.
e place of functional imaging like positron
emission tomography as a diagnostic tool for
primary headache disorders is still undetermined.
As a research tool, these functional imaging studies
have shed light on the possible mechanism of
cluster headaches [63]. A possible central site of
origin of cluster headache has been visualised in the
hypothalamic grey matter [64]. Positron emission
tomography has shown increased blood flow in
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162 Chi Tim HUNG, Steven H.S. WONG
cortical and medial brainstems in migraine without
aura [20–22]. Functional MRI (fMRI) is also useful
in the study of migraine with aura. is might be
more advantageous than other functional imaging
methods because it involves no radioactivity and can
potentially measure multiple parameters including
oxyhaemoglobin saturation [19]. Moderate focal
reductions in cerebral blood flow (32.4%) and
volume in the occipital lobe during spontaneous
migraine visual aura were observed [19].
Electroencephalograph (EEG) has not been
shown to effectively identify headache subtypes
or headaches caused by organic diseases. In a
literature review, Gronseth concluded that EEG is
not indicated in the routine evaluation of patients
presenting with headache [35]. However, EEG may
be indicated in headache patients with alteration
of consciousness, syncopy, head injury or organic
brain syndrome [101].
Some of the common headache disorders are
described below and facial pains are described
in Chapter 11. ese descriptions are not meant
to be comprehensive and readers have to refer
to comprehensive textbooks for all possible
disorders.
Migraine
Migraine is a common episodic headache disorder
that has been under-diagnosed and inadequately
managed [15, 54]. ere is evidence of a hereditary
influence, although not strictly according to the
Mendelian pattern [67]. A family history is present
in 50% of patients.
Clinical features
Migraine affects females more than males (3:1
ratio) with an age of onset commonly between
20 to 40 years [29]. About 25% present before
age 10 years and 10% start with pregnancy [3].
An attack can commence any time, day or night.
Frequency of attack varies from several per week
to several in the entire lifetime and each attack can
last for hours. Typically, a migraine attack can be
divided into five phases, namely prodrome, aura,
headache, resolution and postdrome [10]. It is easy
to recognise migraine when all the five phases are
present. Not all five phases will be seen in every
attack and the headache will be no less debilitating
when only a few phases predominate [91].
e prodrome is experienced in 60% of patients
and can precede the aura by hours or days. e
prodrome consists of changes in mood, behaviour,
gastrointestional symptoms such as craving for
sweets, symptoms of drowsiness and excessive
yawning, thirst or fluid retention, aversions to
odour (osmophobia), light (photophobia) or sound
(phonophobia).
Aura as the hallmark of a migraine attack is
experienced by 10–20% of migraine sufferers. e
ICHD-II (Tables 10.04 and 10.05) recognises
two main types of migraine, namely migraine
with aura (previously called classic migraine)
and migraine without aura (previously called
common migraine). Migraine without aura is the
more common variety. Aura can present as visual
symptoms (Table 10.11) such as teichopsia [14]
or photopsia, scintillating scotoma, hemianopia
and visual hallucinations. It can also present as
auditory or olfactory hallucinations, sensory
and motor symptoms such as hemiparesis. Aura
develops over 5 to 20 minutes and lasts less than
an hour. Headache follows only when neurological
symptoms have subsided. Headache that occurs
together with neurological signs and symptoms
Table 10.04 IHS Diagnostic criteria for migraine
without aura [38]
Diagnostic criteria
A At least five attacks fulfilling criteria B–D
B Headache attacks lasting 4–72 hours and
occurring >15 days/month (untreated or
unsuccessfully treated)
C
1.
2.
3.
4.
Headache has at least two of the following
characteristics:
Unilateral location
Pulsating quality
Moderate or severe pain intensity
Aggravation by or causing avoidance of
routine physical activity (i.e. walking or
climbing stairs)
D
1.
2.
During headache at least one of the following
occurs:
Nausea and/or vomiting
Photophobia and phonophobia
E Not attributed to another disorder
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Headache 163
is ominous (Table 10.02) and deserves further
investigation.
e typical headache is unilateral, throbbing in
character, moderate to severe in intensity and
aggravated by exertion [91]. About half of the
patients experience dull and non-throbbing
headache. Pain may also be bilateral at onset (40%)
or unilateral and then becomes generalised [86].
Headache is often retro-orbital or fronto-temporal
in location. It may radiate to the occipital and
the neck region, confusing the practitioner with
cervical spine disorders or cervicogenic headache.
Migraine headache usually lasts for less than a
day; occasionally it can persist for a few days. e
headache phase is followed by resolution over a
number of hours. Patients may prefer to sleep the
headache off. e postdrome phase then follows
and can last hours to days. e patient is tired with
impaired concentration, irritable and anorexic with
limited tolerance to food. Apart from migraine
with or without aura, other variants include
hemiplegic migraine, vertebrobasilar migraine,
ophthalmoplegic migraine and retinal migraine.
Stress is a known trigger for migraine. Migraine can
also occur during the relaxation phase when the
intense stress is over, e.g. the weekend headache.
Certain types of food like fatty food, chocolate,
and food containing sodium glutamate and nitrates
can trigger an attack. Alcohol, certain vasodilators,
strong odours or changes in weather may also
trigger an attack. e migraine can be precipitated
by menstruation and ameliorated with sleep and
pregnancy [15].
Differentiating between the three primary
headaches may be difficult at times (Table 10.03).
A good history is important. Tension headache and
migraine are sometimes easily confused. e features
most predictive of migraine in contrast to tension
headache are nausea, photophobia, phonophobia,
exacerbation by physical activity and triggering by
food [100]. Cluster headache is a distinct clinical
syndrome with strictly unilateral pain, periorbital
in location and short lasting [100].
Pathogenesis
Understanding the pathogenesis is essential in
formulating treatment. e classic vascular theory
postulated that the aura was due to intracerebral
vasoconstriction and the reactive vasodilatation of
the carotid artery caused the headache of migraine
and cluster headache [33, 111]. e vascular
theory can explain the throbbing character and
the response to ergotamine. It cannot explain the
therapeutic effects of non-vascular drugs such as
non-steroidal anti-inflammatory drugs (NSAIDs)
and tricyclic antidepressants. Recent studies
supported a neurogenic theory whereby neurogenic
inflammation with release of neuropeptides plays
a major role in the pathogenesis [56, 87]. e
observed vasodilation or vasoconstriction is not
a primary event in initiating the headache but an
epiphenomenon. Such neural connections between
the trigeminal nerve and cerebral blood vessels
have been demonstrated [70]. Sensory nerve fibres
that innervate the blood vessels contain Substance
P, calcitonin-gene-related-peptide (CGRP) and
vasoactive intestinal peptide at their terminals.
When a sensory terminal is excited, these vasoactive
peptides are released from other nerve terminals
through an antidromic stimulation, similar to
an axon reflex. Plasma extravasation occurs. It
has been shown that CGRP levels are elevated
in jugular venous blood during migraine attacks
suggesting the relevance of peptide release to the
human condition [53]. e released peptides then
react with the blood vessels that they innervate to
produce vasodilatation. is also causes peripheral
sensitisation and coupled with the central
sensitisation, sensitises the nerve fibres to previously
innocuous stimuli such as blood vessel pulsations.
e neurogenic inflammation also renders the
blood-brain barrier less intact. Apart from peptide
neurotransmitters, nitric oxide released from blood
vessels, perivascular nerve endings and brain has
been postulated to be another molecular mechanism
that triggers spontaneous migraine pain [72].
Neurogenic inflammation does not explain how an
attack starts. is is thought to lie in the increased
brain excitability in migraine patients [4, 108].
Studies using transcranial magnetic stimulation
suggests that occipital cortex neurons may be
hyperexcitable in aura sufferers. is neuronal
hyperexcitability may be due to mitochondrial
defects, disturbance in magnesium metabolism
and calcium channelopathy. e calcium channels
at fault are presynaptic and normally influence the
inhibitory serotonergic system. e hypothalamus
may be involved because of the periodicity. Coupled
with neuronal hyperexcitability, the triggering factors
initiate a depolarising neuroelectric and metabolic
event that spreads across the cerebral cortex like
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164 Chi Tim HUNG, Steven H.S. WONG
the spreading depression of Leao. is spreading
depression forms the basis of the aura [91]. It is
observed that the migraine aura is associated with
a reduction in cerebral blood flow that starts from
the occipital lobe and moves across the cortex. is
spreading oligaemia does not conform to vascular
territory and does not result from vasoconstriction.
Ischaemia rarely occurs during the aura. In fact,
tissue oxygen increases in the early vasodilator
stage of the spreading depression. Migraine aura
is hence more related to neuronal dysfunction
than ischaemia. e spreading depression activates
the trigeminovascular system with antidromic
stimulation, release of vasoactive peptides and then
neurogenic inflammation.
Stimulation of 5HT
1
receptors will turn off
neurogenic inflammation, whereas stimulation of
the 5HT
2
serotonin receptors can lead to migraine
[68]. Drugs that excite 5HT
1
can abort a migraine
attack, whereas drugs that block 5HT
2
receptors
can be used for prophylaxis. e 5HT
1
agonists
act on 5HT
1B
receptors on intracranial arteries
to cause vasoconstriction. ey can also act on
5HT
1D
receptors on meningeal trigeminal sensory
nerve terminals and central terminals of brainstem
sensory nuclei to inhibit nociceptive transmission
[36].
Management
e most important step in management is
making a correct diagnosis. e diagnostic criteria
for different types of migraine are very useful
(Tables 10.04 and 10.05), bearing in mind that
not all patients will present with the classic signs
and symptoms. Avoidance of triggering factors is
important but not always successful. Many a time
the headache is not caused by a single identifiable
trigger, or the trigger is not avoidable [5]. Treatment
of pain is broadly divided into psychological,
pharmacological and physical. A headache diary is
useful to monitor the treatment progress. e role
of interventional therapy for migraine is limited.
Once a diagnosis is made, the patient should be
reassured that the headache is due to a primary
disorder and not ominous causes. is reassurance
has to be repeated every time after negative
imaging tests. ere is as yet no cure for migraine,
although symptoms can be controlled. An adequate
explanation will result in better compliance and
better treatment results.
Ultrasound, transcutaneous electrical nerve
stimulation (TENS), use of hot and cold packs,
massage and stretching exercises can help to relieve
the pain. During headache-free intervals, patients
should be taught how to avoid the trigger factors
like food, prolonged exertion alcohol and drugs. A
change in lifestyle or a wellness programme, such
as regular exercises, balanced meals and adequate
sleep, should be encouraged.
Pharmacological therapy is divided into symptomatic
and prophylactic. Whatever antimigraine drug
treatment is to be instituted, some birth control
measures must be in place for female patients of
childbearing age [15]. e teratogenic potential
of these drugs has not been cleared. Valproate
especially is associated with neural tube defects
[76].
Symptomatic or abortive therapy aims at aborting
an attack (Table 10.06), reducing the severity and
duration of headache and associated symptoms like
vomiting. Prophylactic therapy (Table 10.07) aims
at preventing or reducing the number of attacks.
Depending on the severity of the migraine, most
patients need only abortive treatment. Patients
Table 10.05 IHS diagnostic criteria for Migraine
with aura [38]
Diagnostic criteria
A At least two attacks fulfilling criteria B–E
B Fully reversible visual, sensory, or speech
symptoms but no motor weakness
C At least two of the following characteristics
present:
1. Homonymous visual symptoms including
positive features (i.e. flickering lights,
spots, or lines), and/or negative features
(i.e. loss of vision), and/or unilateral
sensory symptoms including positive
features (i.e. pins and needles) and/or
negative features (i.e. numbness)
2. At least one symptom develops gradually
over ≥5 min and/or different symptoms
occur in succession
3. Each symptom lasts for 5–60 min
D Headache that meets criteria B–D for migraine
without aura begins during the aura or follows
aura with 60 min
E Not attributed to another disorder
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Headache 165
must be taught the proper use of drugs. Overuse of
medications, including analgesics, ergotamine and
possibly sumatriptan, can lead to drug tolerance and
rebound headache (analgesic rebound) on abrupt
withdrawal [84]. Use of abortive drugs should be
limited when possible to two days a week.
Abortive treatment
Abortive treatment is the mainstay of therapy and
ranges from simple analgesics, strong opioids, specific
5HT1 agonists and adjuvants such as prokinetics,
antiemetics and anxiolytics. Prompt treatment is
Table 10.06 Drugs to abort an acute migraine attack
Drug Dose and route Remarks
NSAID
• Acetylsalicylic Acid (mild
attacks)
• Acetaminophen (mild attacks)
• Naproxen
• Ketorolac
• Ibuprofen
• Indomethacin
650–1300 mg PO q4h
650–1300 mg PO q4h
550 mg po stat, then 275 mg every
6–8 hours
30–60 mg IM
400–800 mg PO
25–200 mg PO
50–100mg suppository
Max 4 g/day
Max 4 g/day
Max 1375 mg/day
Max 120 mg/day
Max 2.4 g/day
Max 200 mg/day
Opioids
• Codeine
• Pethidine
• Butorphanol
30–60 mg PO q4h
50–100 mg IM q3h–q4h, max
initial dose 150 mg
Nasal sprays one spray per nostril,
repeat q1h if needed
Not >2 days a week
Not >2 days a week
Max 4 doses/day, not >2days a
week
Sumatriptan 50–100 mg PO, up to 300 mg/24
hours
6 mg SC, up to 12 mg/24 hours
Qd–bd, not >2 days a week.
Qd–bd, not >2 days a week.
Ergotamine 1–2 mg PO at onset
1 mg suppository
Max 3 doses per attack or day
Not to exceed 2 days a week
and 10 mg per week
Dihydroergotamine 0.25–1 mg IM/IV/SC, may be
repeated q1h
Max 3 mg/24 hours
Not >20 ampoules per month
Steroids
• Dexamethasone
• Prednisone
• Methylprednisolone
12–20 mg IV, 16 mg IM
1.5mg PO bd
20 mg qid
4 mg
For 2 days
For 2 days
21 tablets over 6 days
Miscellaneous
• Chlorpromazine
• Midrin (isometheptene 65 mg,
dichloraphenazone 100 mg,
acetaminophen 325 mg) or
Midrid
• Fiorinal (butalbital with aspirin
and caffeine)
50 mg IM
0.1 mg/kg IV infusion over 20
mins, repeated after 15 mins
2 tablets stat and then 1 tablet q1h
1–2 tablets q4h
Max 37.5 mg IV
Max 5 tablets per day, not >2
days a week
Max 6 tablets per day, not >2
days a week
PO = per oral.
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166 Chi Tim HUNG, Steven H.S. WONG
critical in aborting an attack [92]. Special attention
has to be paid to the route of administration of these
drugs. For patients with severe nausea and vomiting
or headache of rapid onset, the oral absorption of
drugs may not be reliable or effective. e parenteral
route, nasal or rectal routes have to be explored. Rest
in a dark and quiet environment during the early
part of headache may help to decrease the duration
of the attack [5].
Despite the importance of pharmacotherapy, not
every migraine attack requires all the use of powerful
drugs with their potential attendant side effects.
It is logical to adopt a stepwise or algorithmic
approach according to the severity of the migraine
[92]. A guideline on the management strategy
will be helpful [76]. For mild attacks of short
duration (<2 hours), resting in a quiet room with
a NSAID and metoclopamide may be adequate.
For moderate to severe headache not responsive to
NSAIDs, ergotamine suppository or subcutaneous
sumatriptan together with antiemetics should be
given. If the headache persists despite sumatriptan,
nasal butorphanol or codeine, together with
chlorpromazine suppository can be prescribed. If
this regimen fails at the outpatient visit, intravenous
metoclopamide with dihydroergotamine, intravenous
ketorolac, intravenous dexamethasone or a parenteral
opioid like pethidine should be tried. Failing that,
or if headache persists for more than 48 hours,
in-patient treatment is indicated using repetitive
dihydroergotamine, intravenous lignocaine and
steroids. Close cardiac monitoring is required under
these circumstances. As with sumatriptan, all other
triptans, dihydroergotamine and ergotamine should
not be given within 24 hours of each other [5]. A
brief description of commonly used medications for
abortive treatment is given below.
Table 10.07 Drugs for prophylactic treatment of migraine
Drug Dose and route Remarks
Beta-blockers
• Atenolol
• Metoprolol
• Nadolol
• Propranolol
50–150 mg/day PO
100–200 mg/day PO
20–120 mg/day PO
60–120 mg/day PO
Calcium channel blockers
• Verapamil
• Flunarizine
120–480 mg/day PO
5–10 mg/day PO
Anticonvulsants
• Sodium valproate
• Gabapentin
• Topiramate
500–1500 mg/day
1800–2400 mg/day
100–200 mg/day
Antidepressants
• Amitriptyline
• Nortriptyline
• Dothepin
• Fluoxetine (SSRI)
10–100 mg/day PO
10–100 mg/day PO
10–120 mg /day PO
20–80 mg/day
NSAID
• Naproxen
• Indomethacin
250–500 mg/day PO
25–200 mg/day PO
Not > 1 week per month
Not > 1 week per month
Cyproheptadine 4–16 mg/day
Methysergide 2 mg PO nocte, gradually to tds,
usually 4–8 mg/day
Resting period needed
Monoamine oxidase inhibitors
• Phenelzine 15–60 mg/day PO
PO = per oral.
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Headache 167
Simple Analgesics
Non-steroidal anti-inflammatory drugs, aspirin
and paracetamol are effective for mild to moderate
migraine and are regarded as first-line drugs.
Patients might have already tried these over-the-
counter medications before consulting a doctor.
However, the response to NSAIDs varies from
patient to patient, and from drug to drug. It is
worthwhile exploring another NSAID if one is
ineffective [84]. A NSAID is the drug of choice
for menstrual migraine. Other types of headache
like exertional migraine, cough headaches, chronic
paroxysmal hemicrania and benign orgasmic
headache also respond to NSAIDs. Combining
different analgesics with different sites of action has
the advantage of reducing the side effects.
Opioids
e role of opioid analgesics in aborting an acute
migraine attack is diminishing. Opioids are useful
for patients where all conservative measures have
failed, and for pregnant patients [68]. Oral codeine
and intramuscular (IM) pethidine can be given.
Recent interest has focused on butorphanol, an
agonist antagonist that can be administered via the
nasal route. Adequate dosing is important.
Triptans
Sumatriptan is the first triptan marketed. It is a
potent, selective serotonin agonist acting at the
5HT1D receptors on the blood vessels for acute
treatment of migraine and cluster headache.
Sumatriptan enters the brain poorly [75, 87].
Presynaptic and post-synaptic serotonin receptors
are present in the central nervous system. Of these,
5HT
1B
and 5HT
1D
are most relevant to migraine
and cluster headache treatment. Sumatriptan
has presynaptic and postsynaptic actions.
Presynaptically, it blocks neuronal transmission and
release of vasoactive peptides from nerve endings,
inhibiting neurogenic inflammation. ere is a
direct postsynaptic action to cause vasoconstriction.
e presynaptic effect is now thought to be more
important.
Oral sumatripan relieves up to 70% of migraine
attacks at 1 hour and subcutaneous injection
relieves up to 77% at 1 hour. e subcutaneous
route acts faster and analgesia is evident in 10
minutes. However, because of the limited duration
of action, the headache may recur in 24 hours in up
to 40% of patients. Usually, patients will respond
to the second dose of sumatriptan.
Sumatriptan is well tolerated and most adverse
effects are transient. e most frequent include
nausea, vomiting, fatigue, malaise or dizziness.
Transient minor pain and redness can occur with
subcutaneous injections. Chest symptoms, mainly
tightness and pressure possibly related to cardiac
ischaemia, are consistently reported in 3–5% of
sumatriptan recipients. ey have been associated
with myocardial ischaemia only in a few isolated
case reports. ese included the development of
transmural infarction in a 43-year-old man after
100 mg sumatriptan and in a 35-year-old woman
with occult coronary artery disease [104].
Sumatriptan is contraindicated in patients with
ischaemic heart disease, uncontrolled hypertension
and pregnancy. Special caution should be taken
when prescribing it to men above 40 years of age
and those with a strong family history of vascular
disease. In those where risk factors for coronary
artery disease are present, the first dose should
be administered under medical supervision.
Sumatriptan should not be taken within 24
hours of administration of dihydroergotamine or
ergotamine
Sumatriptan 50–100 mg orally or 6 mg
subcutaneously should be administered at onset
of headache. If 50 mg is ineffective, the 100 mg
tablet should be taken subsequently. Sumatriptan is
effective at any stage of headache. In migraine with
aura, it should not be taken until the aura ablates
and the actual pain has begun. is might relate to
the fact that sumatriptan enters the brain poorly.
With the neurogenic inflammation, the integrity of
the blood-brain barrier is disturbed allowing more
sumatriptan to get through. e same dose may be
repeated once subcutaneously or twice orally within
24 hours for headache recurrence. e maximum
oral and subcutaneous doses in 24 hours are 300
mg and 12 mg respectively. Sumatriptan is also
available as a nasal spray [55]. e onset of action
is also fast and it is useful for those experiencing
vomiting. However, the nasal preparation is more
likely to induce nausea [5].
Apart from sumatriptan, newer triptans like
rizatriptan, zolmitriptan and naratriptan are
available [5]. ey differ from sumatriptan with
respect to their pharmacological profiles [12].
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168 Chi Tim HUNG, Steven H.S. WONG
Switching from one triptan to another may
improve the success of treatment. Compared with
sumatriptan, rizatriptan may provide better relief
from pain and nausea [24]. While rizatriptan also
has a fast onset of action, naratriptan has the slowest
onset and longest duration of action. Naratriptan
also has the lowest reported incidence of chest
discomfort.
Ergot derivatives
Ergotamine has been used to treat migraine for
a long time. It is an alpha-adrenergic-antagonist,
serotoninergic agonist and vasoconstrictor. Oral,
sublingual and rectal forms are available. e
suppository form of ergot is better absorbed
and recommended. e plasma level after rectal
absorption is 20 times higher compared with the
oral route [15]. It provides good relief if used at onset
of attack. e most effective dose of ergotamine is
the sub-nauseating dose. To determine this dose,
patients are instructed to use one quarter of the
suppository during headache-free intervals, adding
a quarter of a suppository each day until nausea or
the entire suppository is used.
Ergots can cause vasospastic side-effects if the
recommended dose is exceeded. Ergotamine is
contraindicated in renal disease, hepatic disease,
peripheral vascular disease, coronary artery disease
and hypertension. Nausea, vomiting, paraesthesia
and chest discomfort are the major side effects.
Ergot-induced headache (rebound) is a major
problem and the dose of ergotamine should be
limited to no more than 2 days a week and not
exceeding 10 mg per week [90]. Up to two
suppositories or three oral tablets can be taken per
attack. When ergotamine is taken for menstrual
migraine, it can be taken daily during menstruation
and none during the rest of the month.
e use of ergotamine in the treatment of adult
migraine is safe and effective when used in the
recommended doses and in those for whom
contraindications have been excluded [90].
Dihydroergotamine is a derivative of ergotamine
and is also a non-selective 5HT
1
agonist. It is
effective for aborting migraine headaches from
severe to intractable and is the mainstay of therapy
for very severe migraine. e potency to cause
arterial vasoconstriction is less than ergotamine.
Nevertheless it is still a potent venoconstrictor.
Adverse effects, such as vomiting, cramps or
chest pains, are fewer and occur less often than
with ergotamine. ere is a greater tendency to
cause nausea. e duration of action is longer
than sumatriptan, hence it is less likely to cause
headache recurrence. It can be used subcutaneously,
intramuscularly, intravenously or intranasally. For
an acute attack, 0.25 mg to 1 mg of the drug is given
intramuscularly or intravenously up to a maximum
of 3 mg per day. Monthly use should not exceed 12
headache events or 20 ampoules [84].
Dihydroergotamine can also be given in repetitive
intravenous doses over 3 to 7 days as inpatient
treatment for intractable headaches. is is useful
for breaking headache cycles and on occasions
some patients receive up to 20 mg for that week.
Most patients will become headache free and this is
especially effective for cluster headache.
A nasal form of dihydroergotamine was
approved by the FDA in 1998 for use in migraine.
Placebo-controlled trials demonstrated good
clinical effectiveness. At present, the spray is still
cumbersome to use because it has to be filled up
with drug at the time of administration [5, 55].
Miscellaneous medications
Isomethepene is a synthetic sympathomimetic that
has alpha- and beta-adrenergic activity and has
been used for abortive treatment. In commercial
preparations, it is often combined with other drugs
like paracetamol (Midrid) or acetaminophen and
dichloralphenazone (Midrin). It is contraindicated
in glaucoma, renal disease, heart disease and
concurrent monoamine oxidase inhibitor usage.
Butalbital is an intermediate acting barbiturate
combined with acetaminophen or aspirin for
abortive treatment. ese drugs are very effective
when taken intermittently, except for the addictive
potential of butalbital. e use of steroids is
controversial. Randomised placebo-controlled
studies are not available to confirm their efficacy.
Prednisone, hydrocortisone, or methylprednisolone
can be considered for migraine resistant to
conventional treatment [15]. Lignocaine, both
intravenously and intranasally, has been tried.
e effect of intravenous lignocaine, 1 mg/kg is
disappointing [79]. Intranasal lignocaine, using
4% solutions, can relieve the headache and nausea
in 55% of patients, but early relapse of headache is
common [57].
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Headache 169
Adjunctive medications
During an attack, atony and dilatation of the
stomach can cause gastroparesis with delayed
gastric emptying. Concurrent use of prokinetic
agents like metoclopamide or cisapride improves
the gastric motility and increases the efficacy of oral
agents. Metoclopamide has the added advantage
of being an antiemetic. Benzodiazepine may be
added to allay patient’s anxiety. Phenothiazines
like chlorpromazine have been reported to be
efficacious [15].
Prophylactic treatment
Medications for prophylactic treatment carry
with them adverse effects and should be justified.
Prophylactic therapy is indicated in:
• Recurrent migraine that significantly interferes
with the patient’s daily routine despite
abortive treatment (e.g. two or more disabling
attacks a month each lasting 3 or more days,
or infrequent attacks that produce profound
disability)
• Failure of, contraindication to, or troublesome
side-effects from acute medications
• Overuse of acute medications
• Special circumstances, e.g. hemiplegic
migraine or attacks with a risk of permanent
neurologic injury
• Very frequent headaches (more than twice
a week) with the risk of rebound headache
development
• Patient preference, i.e. the desire to have as
few acute attacks as possible [94].
e goals of prophylactic therapy are to:
• Reduce attack frequency, severity, and
duration
• Improve responsiveness to treatment of acute
attacks
• Improve function and reduce disability [95].
While on prophylactic therapy, patients may still
require abortive treatment for the headache.
Many classes of drugs can be employed for
prophylaxis (Table 10.09). Beta-blockers are the
first choice, while methysergide and phenelzine
are regarded as the last resort because of their
adverse effects [69]. e scientific evidence is best
for metoprolol, divalproex, amitriptyline, atenolol,
flunarizine and naproxen [6]. It is important to
start low and go slow [15]. e minimal effective
duration for prophylactic treatment is 1 to 2
months especially with calcium channel blockers.
Prophylactic therapy can be tapered down after 9 to
12 months when symptoms are controlled. A brief
description of the commonly used medications for
migraine prohpylaxis is given below.
Beta-blockers
e mechanism of action of beta-blockers in
reducing the frequency of migraine attacks is
uncertain, but it probably through the 5HT2
receptors. Atenolol, metoprolol, nadolol and
propanolol are effective. ose with intrinsic
sympathomimetic activity are usually not effective.
Contraindications for long-term beta-blockers
include asthma, chronic obstructive airway
disease, insulin dependent diabetes, heart block
and peripheral vascular disease. Special cautions
have to be taken when prescribing beta-blockers
in pregnancy. Changing from one beta-blocker to
another may be useful if the first one is ineffective.
Beta-blockers must not be terminated abruptly as
rebound headaches can occur. Once the disease has
been controlled, the beta-blockers can be gradually
tailed down.
Calcium Channel Blockers
ese drugs act by modulating transmitter release
rather than causing vasodilatation. Although
some investigators consider this as the first-
line prophylactic, the evidence-based support is
lacking. e onset of beneficial effects of calcium
channel blockers is gradual and side effects are
quite substantial. Verapamil and flunarizine are
commonly used. ey are useful in patients who
have migraine with prolonged aura, complicated
migraine, co-existing Prinzmetal angina or
Raynaud’s phenomenon. e efficacy is similar to
beta-blockers.
Contraindications include pregnancy, hypotension,
congestive heart failure, sick sinus syndrome and
atrial flutter or fibrillation.
Anticonvulsants
Different preparations of valproic acids, sodium
valproate and divalproex sodium [61, 104] are
found to be effective for migraine prophylaxis.
Randomised controlled trials have confirmed the
efficacy and some authors have considered this to
be the first-line therapy when there is coexisting
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