DRUGS FOR MIGRAINE

### DRUGS FOR MIGRAINE

(Antimigraine drugs)

# MIGRAINE :-

A disease characterized by pulsating, throbbing headache, often restricted to

one side of the head, episodic in nature, associated with nausea, vomiting,
dizziness, intolerance to light and sounds.

Each attack lasts for few hours usually, but may persist upto 48 hours also.

* Exact pathophysiology of this disease is not completely understood. However,

5HT is believed to play a pivotal role.

* Some triggering event appears to initiate a neurogenic inflammation in the

cranial blood vessels.

The process is amplified by "retrograde transmission" in the afferent nerves and

release of several mediators, notably 5HT and others like Substance P, Nitric
Oxide (vasodilator), Neurokinin, Calcitonin Gene Related Peptide / CGRP
(another potent vasodilator).
The neurogenic inflammatory process causes dilatation of cranial blood
vessels, leakage of plasma from the inflammed vessels, perivascular edema,
stretching of dura mater and stimulation of pain nerve endings in the dura.

# Evidences in support of the role of 5HT:

i) Sharp rise of urinary levels of a major metabolite of 5HT i.e. 5HIAA (5-Hydroxy
Indole Acetic Acid) during attacks of migraine strongly suggests the role of 5HT
in the pathophysiology of the disease.

ii) An acute attack of migraine is controlled by suppressors of serotonergic

neural activity in the brain (e.g. Triptans).

iii) 5HT releasers (e.g. Reserpine) can precipitate an acute attack of migraine.

# Hallmark of Migraine :-

> "EPISODIC" nature of symptoms. The symptoms come in the form of "attacks"
after a certain time intervals.

> Greater is the severity of the disease, lesser is the time interval between two
consecutive "attacks", and greater is the number of attacks per month.
# Classical Migraine (15 - 20% cases):

The patient experiences an "aura" in the form of abnormal visual sensations

("flashes of light") usually 20 - 30 mins before the actual "attack" occurs.

# Migraine without "aura" (80 -85% cases):

Attacks are not preceded by an "aura".

## DRUGS FOR ACUTE ATTACK OF MIGRAINE:

A) TRIPTANS (5HT 1D/1B AGONISTS):

These are first-line drugs. Recommended specially for moderate to severe

migraine where an NSAID or even combinations of NSAIDs may not be
effective. Examples:

i) Sumatriptan

ii) Rizatriptan

iii) Naratriptan
iv) Zolmitriptan

v) Frovatriptan (longest plasma t1/2 among Triptans)

B) ERGOT ALKALOIDS:

i) Ergotamine (oral drug; often combined with Caffeine so as to enhance

absorption)

ii) Dihydroergotamine (parenteral)

C) NSAIDs (Non-steroidal anti-inflammatory drugs):

i) Paracetamol

ii) Ibuprofen

iii) Diclofenac

iv) Indomethacin
D) Adjuvant to Triptans / Ergot alkaloids / NSAIDs:

i) Anti-emetics: (necessary in most cases of moderate to severe migraine):

* Domperidone

* Prochlorperazine

ii) Caffeine: given in combination with Ergotamine to enhance absorption of

Ergotamine.

## Selection of drugs as per severity of Migraine:

A) MILD MIGRAINE (<1 attack per month, each attack lasts around 7 - 8 hours,
but does not incapacitate the patient):

* Therapeutic options:

1) ANALGESICS:

> Paracetamol: 500 mg 6 hourly till relief

OR

> Some other NSAID either alone, or in combination with Paracetamol.

Examples:

i) Ibuprofen (400 mg 8 hourly)

or

ii) Diclofenac (50 mg 8 hourly) or

or

iii) Indomethacin (50 mg 8 hourly)

2) Anti-emetics (for vomiting): may/may not be required. Depends upon

symptoms.

B) MODERATE MIGRAINE (1 or more attacks per month, each attack lasts

between 6 - 24 hours, activities of the patient are compromised during each
attack):

* Therapeutic options:

1) ANALGESICS:
> Paracetamol alone will not be sufficient.

> Either a combination of NSAIDs is used

OR

Any one of the "Triptans" (Sumatriptan/ Naratriptan/ Rizatriptan/ Zolmitriptan)

is advised.

2) Antiemetics: necessary because the accompanying nausea and vomiting is

usually marked. Options:

i) Domperidone (D2 receptor blocker):-

> The drug does not cross BBB. Hence, it does not cause extrapyramidal side
effects (e.g. Drug-induced Parkinsonism).

> Anti-emetic effect is achieved by blocking D2 receptors in the CTZ because

CTZ lies outside the BBB.

ii) Prochlorperazine (Phenothiazine derivative):

> It is a central D2 receptor blocker with additional antihistaminic action. It is
also a labyrinthine suppressant.

> Actions: anti-emetic and anti-vertigo.

> The "sedation" caused by this drug (due to antihistaminic action) is an

advantage during an acute attack of migraine.

> However, extrapyramidal disturbances may occur. Acute muscle dystonia (an
extrapyramidal side effect) can occur, specially after i.m. injection. Children are
particularly prone to dystonia and should not be given i.m. injection of this drug.

> Mouth-dissolving tablets is a safer and preferable option for nausea &
vomiting.

3) If the number of attacks per month is more than 2, prophylactic drugs may
be required (details given below).

C) SEVERE MIGRAINE (> 3 attacks per month, episodes last around 12 - 48

hours, patient is grossly incapacitated during each attack):

1) Triptans or Ergot alkaloids have to be used, since NSAIDs are usually not
effective in such severe cases.
2) Anti-emetics are required since nausea and vomiting is marked.

3) Prophylactic drugs are necessary for at least 6 months, to reduce the

frequency of attacks.

** [Before studying the mechanism of action of Triptans, have a quick look at

the various pathophysiological components of migraine].

## Pathophysiological components:

1) Release of vasoactive neuropeptides by the trigeminovascular system

(Neurogenic inflammation).

2) Dilatation of cranial blood vessels. When

carotid arterio-venous shunts dilate during an acute attack, this shunts blood
away from the brain parenchyma and results in generation of hypoxic
metabolites.

3) Leakage of plasma from the inflammed vessels results in perivascular

edema, dural stretching and stimulation of pain nerve endings in the dura.

4) Nociceptive neurotransmission within the trigeminal nerve is increased.

* These pathophysiological processes can be reversed by agonists at 5HT
1D/1B receptors. These receptors are inhibitory autoreceptors and suppress
abnormal serotonergic neural activity in the brain.

## TRIPTANS IN ACUTE ATTACK OF MIGRAINE

#MECHANISM OF ACTION OF TRIPTANS:

* Triptans are 5HT1D/1B receptor agonists. These receptors are inhibitory pre-
synaptic receptors (autoreceptors).

Triptans reduce abnormal serotonergic activity in and around cranial blood

vessels and suppress neurogenic inflammation of cranial blood vessels.

* Triptans control the manifestations of an acute attack of migraine in the

following ways:

1) Dilated cranial blood vessels undergo constriction, specially the carotid

arterio-venous shunts which express 5HT 1D/1B receptors.

Constriction of carotid arterio-venous shunts prevents diversion of blood away

from the brain parenchyma. Consequently, generation of hypoxic metabolites
and hypoxic insult to the brain parenchyma is prevented.

2) Being 5HT 1D/1B agonists, Triptans inhibit the release of inflammatory

neuropeptides around the affected vessels and also suppress extravasation of
plasma proteins across dural vessels.

These actions prevent stretching of the dura and stimulation of pain nerve
endings.

3) Triptans also block the activation of trigeminal nerve terminals at the

meninges and inhibit nociceptive neurotransmission.

# SUMATRIPTAN (prototype drug)

* 5HT 1D/1B agonist.

* Dose for acute attack of migraine:

50 - 100 mg (oral) at the onset of an attack. Dose may be repeated once again
within next 24 hours if symptoms do not subside after first dose.

The 2nd dose is usually given after 2 hours of the first dose, if the symptoms do
not subside with the first dose.
* Routes: Oral, subcutaneous, intranasal.

> Oral bioavailability is poor. Nonetheless, oral route is still used and higher
doses (50 - 100 mg each time) are needed.

> Bioavailability after s.c. administration is much higher. Just 6 mg s.c. is

sufficient.

However, s.c. injection is painful and has higher chances of causing tightness in
the chest, dizziness, and paraesthesia (tingling sensation) in the limbs.

** Note: Sumatriptan is the only Triptan which is available for parenteral use.

> Nasal spray: onset of action is faster than oral, but bioavailability is poorer
compared to the s.c. route. Around 25 mg is needed each time. Bitter taste in
the mouth may be felt after using nasal spray.

* Sumatriptan is metabolized by MAO-A. Its elimination half-life is around 2

hours.

* Side Effects: (more common after s.c. injection):

i) Tightness in the chest

ii) Paraesthesias in the limbs

iii) Dizziness

iv) Weakness

* However, the above side effects are usually short-lasting and dose-related.

* BP may be increased slightly, but this is not significant because Sumatriptan

is not consumed on regular basis. It is used just to provide relief during an
acute attack of migraine.

* Contraindications:

i)* Ischaemic Heart Disease

(Sumatriptan can precipitate AMI i.e. Acute Myocardial Infarction)

ii) Uncontrolled hypertension

iii) Epileptic patients (seizures may be precipitate)

iv) Hepatic / Renal impairment

v) Pregnancy

## RIZATRIPTAN:

* Advantages over Sumatriptan:

i) Higher potency

ii) Better oral bioavailability

iii) Faster onset of action

* Dose: 5 - 10 mg at the onset. If necessary, the dose may be repeated after 2

hours.
## ERGOT ALKALOIDS IN ACUTE ATTACK OF MIGRAINE

* These also possess agonistic action at 5HT 1D/1B and exert actions similar
to Triptans:

i) Constrict carotid A-V shunts. Prevent diversion of blood away from the brain
parenchyma and prevent hypoxic insult.

ii) Suppress release of inflammatory neuropeptides in cranial blood vessels.

iii) Prevent stretching of dura mater due to leakage of plasma from cranial
blood vessels.

* Rationale behind combination of Ergotamine (1mg) and Caffeine (100 mg) in

oral formulations:

i) Caffeine enhances absorption of Ergotamine.

ii) Caffeine itself is capable of causing vasoconstriction in cranial blood

vessels.

iii) Caffeine is a psychic stimulant. It can make the patient feel better.
* Source of Ergot derivatives:

Claviceps purpurea (a fungus).

* Current status of Ergot derivatives:

> These are far less popular than Triptans.

> Ergot alkaloids themselves cause nausea & vomiting. This is a major
disadvantage since nausea & vomiting are features of migraine itself.

>** Ergot alkaloids should not be used on a regular basis since they produce a
dull background headache. Discontinuation may precipitate an attack of
migraine.

> Ergot alkaloids (particularly Ergotamine) cause multiple other adverse effects
like:

i) Muscle cramps

ii) Precordial pain (due to coronary vasoconstriction)

iii) Risk of hypersensitivity reactions (localized edema, pruritic skin rashes)

iv) Marked paraesthesia (numbness & tingling) in fingers and limbs

v) Overdose is highly risky. It results in intense peripheral vasoconstriction plus

damage to capillary endothelium. This can lead to vascular stasis, thrombosis,
and even gangrene of the extremities.

> Dihydroergotamine is recommended for parenteral use. It is relatively safer

than Ergotamine. Vascular complications are less severe.

> Overall, the availability of better and much safer drugs like the Triptans have
made Ergot derivatives even less popular.

> Ergot derivatives are considered only if the cost of Triptans is a factor or if
Triptans are not giving the desired level of success. Dosage of ergots should be
cautious. Overdose must be avoided.

* Dose of Ergotamine + Caffeine combination: One tablet at the onset of attack.

May be repeated after 30 mins only if necessary.

## DRUGS FOR PROPHYLAXIS OF MIGRAINE:

* These drugs DO NOT control symptoms during an acute attack.

* These drugs are to be taken AFTER the acute attack has been taken care of.

In other words, these drugs are to be taken on a regular basis after an acute
episode is controlled with Triptans/ NSAIDs/ Ergot.

* The purpose of giving prophylactic drugs is to reduce the frequency and/or

severity of attacks in future i.e. to prolong the interval between attacks and
reduce the severity of future attacks.

* Prophylaxis is recommended in moderate to severe migraine cases having 3

or more attacks per month.

* Once started, prophylactic drugs should continue for at least 6 months.

Thereafter, they may be discontinued JUST TO CHECK if attacks of migraine
recur and with what severity they recur. This will decide whether prophylactic
drugs need to be continued.

In the meantime, patients should try best to avoid precipitating factors like:
stress, anxiety, alcohol, OCPs, tyramine-rich foods like cheese, chocolates.

# Drugs recommended for prophylaxis:

A) NON-SELECTIVE BETA BLOCKERS:

* Propranolol (most commonly used drug). Started at 40 mg twice daily. Can be

increased upto 160 mg twice daily.

* Timolol (alternative drug)

* Exact mechanism of non-selective Beta Blockers in prophylaxis of migraine is

still unknown.

* Efficacy of Propranolol in prophylaxis of migraine has been found superior to

other drugs used for this purpose, e.g. Verapamil, Anticonvulsants (Sodium
Valproate, Topiramate etc.).

B) TRICYCLIC ANTIDEPRESSANT (TCA):

* Amitryptiline: 25 - 50 mg at bedtime.

* Again, the exact mechanism in migraine prophylaxis is still not known.

* Role in prophylaxis of migraine is independent of its antidepressant action.

However, this drug has been found to be particularly beneficial in patients who
have features of depression with migraine.

* Efficacy of Amitryptiline is notable, but it is a less safer option than

Propranolol because side effects are more.

C) CALCIUM CHANNEL BLOCKERS (CCB):

* Options: VERAPAMIL, FLUNARIZINE**

* Flunarizine (10 - 20 mg once daily): It is a cerebro-selective CCB which

benefits migraine patients by reducing intracellular Ca++ overload caused by
brain hypoxia.

D) ANTICONVULSANTS:

* Options:

i) Sodium Valproate (400 - 1200 mg/day)

ii) Gabapentin (300 - 1200 mg/day)

iii) Topiramate (25 - 50 mg once daily)

* Efficacy of anticonvulsants is inferior to Propranolol. They are used if

Propranolol is contraindicated or poorly tolerated.

E)** ERENUMAB (new drug):

* Human monoclonal antibody.

* Target of action: CGRP- antagonist.

(CGRP: Calcitonin Gene Related Peptide; potent vasodilator, one of the

mediators of neurogenic inflammation)

* Advantage: Just ONCE MONTHLY s.c. injection reduces frequency of attacks.

* Availability and high cost of monoclonal antibodies are its drawbacks.

F) Methysergide: 5HT antagonist; not used now because of risks of endocardial

& pulmonary fibrosis.