Drugs used in headache and Migraines.

INTRODUCTION
• Headache is a painful sensation in any part of the head ranging from
sharp to dull, that may occur with other symptoms.
• Headache is a very common condition that most people will
experience many times during their lives.
• Headache is generally caused by stimulation, irritation or agitation of
blood vessels near the Dura matter, Cranial Nerve V and blood vessels
near muscles of head and neck respectively.
 CLASSIFICATION OF HEADACHES
• Headaches occur in different forms
• However all these forms can be grouped into two groups
- Primary headaches
-Secondary headaches
 PRIMARY HEADACHES
• Primary headache is when the head itself is the problem.
• it is not a symptom of an underlying disease or condition.
• It is usually occurs due to an over activity of or problems with pain
sensitive structures in your head.
• Some notable types of Primary headaches include:
- Migraine
- Cluster headache
-Tension headache
 MIGRAINE
• Is the second most common type of headache after Tension type
headache.
• Migraine headache has the following characteristics
-Pulsatile (Associated with Phonophobia and Photophobia)
-One day duration
-Unilateral
-Nausea/Vomiting (Associated with:)
- Disabling
• Migraine can be of two types
-Migraine with aura
-Migraine without aura
But, what is an aura?
• Aura is a collection of symptoms or sensations such as flashing lights or
zigzag lines, which typically precede migraine headache, seizures or
other neurological events.
• Aura are caused by spread of wave of depolarization, and its
presentation depends on the area of the brain affected most by this
wave spread.
• If the occipital lobe is affected most one will have visual auras (Most
common type of aura in migraine), Visual auras can be Scotoma, bright
dots, zig zag lines etc.
• If the sensory cortex is affected most one will present with paresthesia.
• If the motor cortex is affected most one will present with weakness on one
side of the limb (Hemiplegic migraine, Familial type, usually mistaken with
stroke)
• If the brainstem is affected one will have brain stem auras presented with
Diplopia, vertigo, Decrease hearing, dysarthria
• NB: Sometimes one can have auras without migraine.

Visual aura: Scotoma

 Pathophysiology of Migraines
• The exact cause of migraine is unknown.
• However migraine is known to be triggered by a vast number of
factors such as lack of sleep, Increase in stress, dietary choices such
as red wine, cheese, chocolate, strong scents, shift in weather,
hormonal changes during woman menstrual cycle, among others.
• Some scientist believe that there are also a number of internal
triggers.
• According to Cortical Spreading depression theory these triggers
causes neurons in the brain to fire abnormally (The reason why these
particular triggers will cause abnormal neurone firing in one person
and not another is unknown)
• NB: Only hemiplegic migraine has been traced back to reveal
associations with genes.
• This abnormally firing neurons cause hyper excitability that cause
spread of wave of depolarization through out the brain leading to
symptoms that affect senses.
• One may experience nausea, sensitivity to light and sound or difficult
motor skills and speech, Some people experience auras.
• During the spread of the wave of depolarization there is activation of
certain pain receptors (nociceptors of cranial nerve V) This trigger the
release of Vasoactive peptides (VP), Calcitonin Gene Regulating
Peptide (CGRP) and Substance P.
• VP, CGRP and substance P stimulate mast cells to release histamine
and prostaglandins which induce inflammation.
• VP, CGRP and substance P also act on blood vessels causing
vasodilation and increased permeability of blood vesses
• The end result of the activity of these chemical substances is
activation of other nearby pain receptors.
• The efferent pain signals are picked by CN V and carried to the
trigeminal nucleus then to the thalamus and finally to the cerebral
cortex where it is perceived as headache
• Researches has shown that, people experiencing migraine appear to
have low levels of serotonin.
• Low serotonin induce vasodilation which increase vessels
permeability and activation of nearby nociceptors following the path
as described above.
 CLUSTER HEADACHE
• This is the least common type of headache
• It is usually unilateral, Orbital/Supraorbital
• Can also occur on frontal region
• The pain is usually stabbing, Burning, and sharp.
• Duration is 5 minutes to 3 hours
• One can have 1 to 8 episodes per day and stay up to 12 months without
another attack
• It is associated with ANS effects such as Rhinorrhea and Lacrimation .
• One tends to be restless
 Pathophysiology of Cluster headache:
• Cluster headache is believed to be triggered by Tobacco smoking, Red wine,
being male, stress etc.
• Dysfunctional hypothalamus is a key in this type of headache, which is
stimulated by these triggers leading to its activation.
• Activated hypothalamus sends signals down the parasympathetic system
through parasympathetic fibers to the sphenopalatine ganglion.
• Sphenopalatine ganglion has fibers going to particular areas including
lacrimal glands and nasal glands leading to lacrimation and nasal secretion
respectively.
• Parasympathetic stimulation on the small blood vessels stimulate neurogenic
inflammation which will lead to stimulation of nearby nociceptors which will
be picked as efferent signals by the CN V through the trigeminal nucleus to
the thalamus and finally cerebral cortex..
 TENSION HEADACHE
• The most common type of headache.
• Caused by several triggers such as muscle being tight /tender,
dehydration, stress, or lack of sleep.
• These triggers cause muscles near the paracranial area to become
tight ,stiff and tender.
• When these muscles become tight, activate blood vessels near these
muscles. Activation of these blood vessels stimulate nociceptors
nearby.
• The efferent signals are picked by the CN V, to the trigeminal nucleus
to the thalamus and finally to the cerebral cortex where they are
perceived as headache.
 SECONDARY HEADACHE
• These are headaches due to an underlying medical condition.
• The underlying condition can be a mass occupying space in the brain,
CNS pathology or External CNS pathology.
• Mass occupying lesions can be increase in blood, brain tissue or CSF.
• Increase in blood to the cerebral vessels as in hypertension, or blood
clots in the brain tissue in cases of hematoma caused by trauma
(Subdural hematoma, Epidural Hematoma).
• Increase in brain tissue whether normal or abnormal as in case of
tumors of the pituitary gland (pituitary adenoma) or brain tumor
(Glioblastoma Multiforme, Meningioma)
• Increase in CSF as in hydrocephalus.
• CNS pathology causing headache include Meningitis, Encephalitis,
Cerebral Venous Sinus Thrombosis (C.V.S.T) and Idiopathic Intracranial
Hypertension.
• External CNS disorder causing headache include Sinusitis, Acute angle
closing Glaucoma, Giant cell arteritis, Trigeminal Neuralgia and others
• Secondary headaches are usually associated with other systemic
symptoms such as fever in meningitis and encephalitis, nausea and
vomiting in mass occupying lesions which cause increase in
Intracranial pressure etc.
• These should help in diagnosis.
• There are mainly three classes of drugs used to treat headaches and
migraine.
-Non Steroidal Ant inflammatory drugs (NSAIDs)
-Ergots
-Triptans

• However there are also prophylactic agents for migraine

 NON STEROIDAL ANT-
INFLAMMATORY DRUGS
(NSAIDs)
• NSAIDs are a first line treatment for mild to moderate migraine.
Examples of NSAIDs that can be used in this case include Aspirin,
Ibuprofen, Naproxen and Diclofenac
• Acetaminophen is not an NSAID but common Over The Counter pain
medication that may help with migraine pain.
Aspirin
• A common non steroidal anti inflammatory drug to stop the
progression of migraine.
• Typically a person takes a single dose as they feel symptoms
developing.
• The aim is to prevent the progression of the migraine to reduce pain.
• Aspirin may also work as preventive medication when taken daily at
lower doses although evidence on the effectiveness of this approach
is mixed.
• Aspirin works by blocking an enzyme that makes the body produce
prostaglandins which are compounds with many bodily functions
including inflammation and pain processes.
• By stopping this production processes, aspirin can control pain and
inflammation.
• People generally uses aspirin for mild to moderate migraine that
does not trigger nausea or vomiting, as vomiting may mean that they
do not absorb the medication.
• Those who experience vomiting during migraine episodes may need
anti-emetics to ensure the body can absorb other medicine
• People using aspirin as treatment for current migraine symptoms can
take a single high dose between 900-1300mg
• Side effect: Many people who take aspirin tolerate it well at safe
dosages, however as with oral NSAID it can lead to side effects
• The most common side effects of aspirin are : Digestive irritation,
Indigestion, and nausea
• Less commonly people can experience: worsened asthma symptoms,
shortness of breath and tinnitus
• Rarely severe adverse effect include: Ulcers, Gastrointestinal, and
severe allergic reactions
• Contraindications: Children under 12 years, Children and adolescents
with symptoms of flu or chicken pox, people with stomach ulcers,
people who allergic or sensitive to NSAID, people with bleeding
disorders such as hemophilia, people who are pregnant unless
otherwise instructed by doctor.
Ibuprofen
• Ibuprofen is another NSAID used to relieve headaches in migraine.
• It works by blocking your body production of certain natural
substances that cause inflammation, this effect helps to decrease
pain.
• Over the counter ibuprofen comes as 200mg tablet or chewable, It is
also available as liquid for children.
• For adult with mild to moderate headache pain, taking 200mg of
ibuprofen every 4 to 6 hours might help.
• Taking it up to 3 times per day is enough to bring relief to many
healthy adults (as well as kids over 12)
• It is a reversible cyclo-oxygenase inhibitor, but causes rather less
gastric irritation than aspirin and other NSAIDs at normal doses.
• It can cause other adverse reactions common to the NSAIDs,
including reversible renal impairment in patients who are elderly or
have cirrhosis, nephrotic syndrome or heart failure.
• It reduces the efficacy of antihypertensive medication and of
diuretics by blocking formation of vasodilator and natriuretic
prostaglandins in the kidney
Naproxen
• Another NSAID used to treat acute to mid migraine headaches
• MOA: Naproxen is approximately 20 times as potent an inhibitor of
COX as aspirin.
• Adverse effects: Naproxen causes all of the adverse effects common
to NSAIDs.
Diclofenac
• Diclofenac is used to treat acute migraine attacks with or without
aura in adults.
• It will not prevent or lessen the number of migraine aattacks
• Available in capsule, tablets.
• Mechanism of action and side effects are the same as other NSAIDs
Ketorolac
• This arylacetic acid NSAID has potent analgesic but modest anti-
inflammatory activity.
• MOA: Like other NSAIDs, it inhibits PG synthesis and relieves pain
primarily by a peripheral mechanism.
• PK: Ketorolac is rapidly absorbed after oral and i.m. administration.
• It is highly plasma protein bound and 60% excreted unchanged in
urine.
• Major metabolic pathway is glucuronidation;
• plasma t½ is 5–7 hours.
• Dosage: 15–30 mg i.m. or i.v. every 4–6 hours (max. 90 mg/day).
• Adverse effects: Nausea, abdominal pain, dyspepsia, ulceration, loose
stools, drowsiness, headache, dizziness, nervousness, pruritus, pain at
injection site, rise in serum transaminase and fluid retention
• Contraindication: it should not be given to patients on anticoagulants.
 ERGOT ALKALOIDS
Ergotamine (oral/sublingual) and
Dihydroergotamine(parenteral),a semisynthetic derivative of
ergotamine
These are ergot alkaloids approved for treatment of migraine
headache
The action of ergot alkaloids is complex, with ability to bind
to 5-HT1(B/D) receptors,α receptors and dopamine receptors
5-HT1 receptors located on intracranial blood vessels are
targets that cause vasoconstriction with the use of these
agents
ERGOTAMINE
• Most effective ergot alkaloid for migraine ,most effective
when used in early stages of migraine
• Given early in attack and lower doses suffice, but when pain
has become severe-larger doses are needed and control may
be achieved only after few hours
• Act by constricting the dilated cranial vessels or by specific
constriction of carotid A-V shunt channels
• Caffeine enhances the absorption of ergotamine and is a
powerful vasoconstrictor, so usually combined with
ergotamine
• 2mg SL followed by 1-2mg q30min until attack abated ;not to
exceed 6mg/day and no more than 10mg/week because has
ability to cause dependence and rebound headache
• Combination of ergotamine and caffeine as oral tablet is
Cafergot (1mg/100mg)
• Combination of ergotamine and caffeine as oral suppository
is Migergot (2mg/100mg)
• Metabolism by liver CYP3A4;90% excreted in bile
DIHYDROERGOTAMINE
• Compared to ergotamine ,demonstrates greater alpha
adrenergic antagonist activity, lower arterial
vasoconstriction, less dopaminergic agonism and lower
emetic potential
• Indicated for acute treatment of migraine headache with or
without aura, and acute treatment of cluster headache
episodes
• 1mg IV/IM/SC q1hr;not to exceed 2mgIV or 3mg IM/SC per
24hr episodes. Not to exceed 6mg qweek
• Metabolized in liver by CYP3A4
• Excreted mainly in faeces ,urine <10%
• For nasal spray (Migranal) dosage form;
One spray in each nostril followed by another spray in each nostril
after 15 minutes. Each spray contains 0.5mg of DHE
• Contraindication
In patients with angina, hypertension and peripheral
vascular disease because they are significant
vasoconstrictors
Concomitant strong CYP3A4 inhibitors ( ritonavir,
erythromycin, clarithromycin) because increase risk of
vasospasm leading to cerebral ischemia and/or ischemia of
extremities
Pregnant and lactating mothers
Impaired hepatic or renal function
• Adverse effects are nausea,vomiting,diarrhea,coronary
spasm,ergotism
Serotonin1B/1D Receptor Agonists (Triptans)
• The serotonin1B/1D receptor agonists, also known as triptans, are
first-line drugs for terminating a migraine attack. These agents relieve
pain by constricting intracranial blood vessels and suppressing release
of inflammatory neuropeptides. All are well tolerated. Rarely, they
cause symptomatic coronary vasospasm.
 Sumatriptan
• Sumatriptan [Imitrex, Sumavel DosePro] was the first triptan available and will
serve as our prototype for the group. The drug can be administered by mouth,
nasal inhalation, or subQ injection.

• Mechanism of Action. Sumatriptan, an analog of 5-HT, causes selective

activation of 5-HT1B and 5-HT1D receptors (5-HT1B/1D receptors). The drug
has no affinity for 5-HT2 or 5-HT3 receptors, nor does it bind to adrenergic,
dopaminergic, muscarinic, or histaminergic receptors. Binding to 5-HT1B/1D
receptors on intracranial blood vessels causes vasoconstriction. Binding to 5-
HT1B/1D receptors on sensory nerves of the trigeminal vascular system
suppresses release of CGRT, a compound that promotes release of
inflammatory neuropeptides. As a result, sumatriptan reduces release of
inflammatory neuropeptides and thereby diminishes perivascular
inflammation. Both actions—vasoconstriction and decreased perivascular
inflammation—help relieve migraine pain.
Therapeutic Use.
• Sumatriptan is taken to abort an ongoing migraine attack. The drug
relieves headache and associated symptoms (nausea, neck pain,
photophobia, phonophobia). In clinical trials, sumatriptan gave
complete relief to the majority of patients. Beneficial effects begin
about 15 minutes after subQ or intranasal dosing and 30 to 60
minutes after oral dosing.
• In addition to migraine, sumatriptan is approved for cluster
headaches.
Pharmacokinetics.
• With oral or intranasal dosing, bioavailability is low (about 15%). The
transdermal system has even lower bioavailability (about 6%),
whereas with subQ dosing, bioavailability is high (97%). As a result,
oral and intranasal doses are considerably higher than subQ and
transdermal doses.
• Sumatriptan undergoes extensive hepatic metabolism, primarily by
monoamine oxidase (MAO), followed by excretion in the urine. The
half-life is short—about 2.5 hours.
 Adverse Effects.
• Sumatriptan is generally well tolerated. Most side effects are transient
and mild. Coronary vasospasm is the biggest concern.
• Chest Symptoms. About 50% of patients experience unpleasant chest
symptoms, usually described as “heavy arms” or “chest pressure” rather
than pain. Possible causes are pulmonary vasoconstriction, esophageal
spasm, intercostal muscle spasm, and bronchoconstriction.
Coronary Vasospasm.
Very rarely, sumatriptan and other triptans can cause angina secondary to
coronary vasospasm. Electrocardiographic changes have been observed in
patients with coronary artery disease (CAD) or Prinzmetal’s (vasospastic)
angina.
To reduce the risk of angina, avoid sumatriptan in patients with risk factors
for CAD until CAD has been ruled out. These patients include
postmenopausal women, men older than 40 years, smokers, and patients
with hypertension, hypercholesterolemia, diabetes, or a family history of
CAD.
Owing to the risk of coronary vasospasm, sumatriptan is contraindicated for
patients with a history of ischemic heart disease, myocardial infarction (MI),
uncontrolled hypertension, or other heart disease.
Teratogenesis.
• Teratogenesis. Sumatriptan should be avoided during pregnancy.
• Accordingly, unless the prescriber directs otherwise, women should
be instructed to avoid the drug if they are pregnant or think they
might be, if they are trying to become pregnant, or if they are not
using an adequate form of contraception.
• Sumatriptan is classified in U.S. Food and Drug Administration (FDA)
Pregnancy Risk Category C.
Other Adverse Effects.
• Mild reactions include vertigo, malaise, fatigue, and tingling
sensations. Transient pain and redness may occur at sites of subQ
injection.
• The intranasal formulation tastes bad and may irritate the nose and
throat.
Drug Interactions
• Ergot Alkaloids and Other Triptans.
Sumatriptan, other triptans, and ergot alkaloids (e.g., ergotamine,
dihydroergotamine) all cause vasoconstriction. Accordingly, if one
triptan is combined with another or with an ergot alkaloid, excessive
and prolonged vasospasm could result.
Accordingly, sumatriptan should not be used within 24 hours of an
ergot derivative or another triptan.
Monoamine Oxidase Inhibitors.
• Monoamine oxidase inhibitors (MAOIs) can suppress hepatic
degradation of sumatriptan, causing its plasma level to rise. Toxicity
can result. Accordingly, sumatriptan should not be combined with an
MAOI and should not be used within 2 weeks of stopping an MAOI.
Selective Serotonin Reuptake Inhibitors (SSRIs) and
Serotonin/Norepinephrine Reuptake Inhibitors
(SNRIs).
• the SSRIs (e.g., fluoxetine [Prozac]) and SNRIs (e.g., duloxetine
[Cymbalta]) indirectly activate serotonin receptors in the brain (by
increasing the availability of serotonin at brain synapses). If receptor
activation is excessive, serotonin syndrome can occur.
• Signs and symptoms include altered mental status (agitation,
confusion, disorientation, anxiety, hallucinations, poor concentration)
as well as incoordination, myoclonus, hyperreflexia, excessive
sweating, tremor, and fever. Deaths have occurred. Accordingly, these
combinations should not be used.
Other Serotonin1B/1D Receptor Agonists
• In addition to sumatriptan, the triptan family includes six other drugs:
naratriptan [Amerge], rizatriptan [Maxalt], zolmitriptan [Zomig],
almotriptan [Axert], frovatriptan [Frova], and eletriptan [Relpax].
• All six are administered orally, and one—zolmitriptan—is also given
by nasal spray.
• All six are essentially equal to sumatriptan with respect to efficacy
and safety, and all have the same mechanism of action: activation of
5-HT1B/1D receptors with subsequent intracranial vasoconstriction
and decreased perivascular inflammation. All are in FDA Pregnancy
Risk Category C.
 AGENTS USED IN PROPHYLAXIS OF MIGRAINE
• Therapy to prevent migraine is indicated if the attacks occur two
or more times a month and if headaches are severe or
complicated by serious neurological signs.
• Diverse classes of drugs are used but none is effective in all cases,
and none abolishes the attacks totally. It may be prudent to
discontinue prophylaxis every 6 months to check whether its
continuation is needed or not.
• It is important to avoid the precipitating factor(s).
Several classes of drugs are effective in reducing the frequency
and severity of migraine attacks:
• β-Blockers: Propranolol and nadolol.
• Anticonvulsants: valproic acid and topiramate
• Tricyclic antidepressant: Amitriptyline
• Calcium-channel blocker: Verapamil and Flunarizine
• 5-HT antagonists: methysergide and cyproheptadine
• botulinum toxin A
 β-Blockers

• According to 2022 regime,Propranolol is the drug of choice,

but other β-blockers, particularly nadolol, timolol, atenolol,
metoprolol and nadolol have been shown to be effective.
• Propanolol reduces frequency as well as severity of attacks in
upto 70% patients. Effect is generally seen in 4 weeks and is
sustained during prolonged therapy. The starting dose is 40
mg BD, which may be increased upto 160 mg BD if required
• The mechanism of action is not clear; that it is due to β
adrenergic blockade has been questioned.
 Anticonvulsants
• Valproic acid (400–1200 mg/day) and gabapentin (300–1200
mg/day) have some prophylactic effect in migraine. The
newer drug topiramate has recently been approved for
migraine prophylaxis.
• Efficacy of anticonvulsants in migraine is lower than that of β
blockers. They are indicated in patients refractory to other
drugs or when propranolol is contraindicated.
• They inhibit Na+ channels on axon and re3duce action
potential for release of substance P,CGRP release and
vasoactive peptide.
 Tricyclic antidepressants

• Many tricyclic compounds of which amitriptyline (25–50 mg

at bed time) has been most extensively tried to reduce
migraine attacks. It is effective in many patients but produces
more side effects than propranolol.
• Mechanism of action is by modulating serotonergic
transmission by blocking reuptake of the transmitter.
 Calcium-channel blocker
• Verapamil was found to reduce migraine attacks,
• It is claimed to be a cerebro-selective Ca2+ channel blocker;
may benefit migraine by reducing intracellular Ca2+ overload
due to brain hypoxia and other causes
• Side effects are sedation, constipation, dry mouth,
hypotension, flushing, weight gain and rarely extrapyramidal
symptoms.
• Flunarizine is a relatively weak Ca2+ channel blocker that
also inhibits Na+ channels. It is claimed to be as effective as
propranolol
• Dose: Flunarizine 10–20 mg OD, children 5 mg OD
 5-HT antagonists
• 5-HT antagonists The prophylactic effect of methysergide
and cyproheptadine is less impressive than β blockers. They
are seldom used now for migraine.
• Methysergide is a potent 5-HT2A/2C antagonist; but is
nonselective—acts on 5-HT1 receptors also. Prolonged use
has caused abdominal, pulmonary and endocardial fibrosis
• Ketanserin It has selective 5-HT2 receptor blocking property
with negligible action on other receptors.
 Botulinum toxin A

• Localized injection of minute quantity of botulinum toxin A

(BOTOX) or Onabotulinum toxin A has recently been
approved for prophylaxis for chronic migraine where
headaches occur for more than 14 days per month.
• It is given every 12 weeks as multiple injections around the
head and neck to try to dull future headache symptoms
• It inhibits release of acetycholine (pain signals)
Thank you.