A Textbook of Clinical Pharmacology and Therapeutics

●Pathophysiology 142

●Drugs used for the acute migraine attack 142

●Drugs used for migraine prophylaxis 143

CHAPTER 23

MIGRAINE

PATHOPHYSIOLOGY

Migraine is common and prostrating, yet its pathophysiology
remains poorly understood. The aura is associated with intracra-
nial vasoconstriction and localized cerebral ischaemia. Shortly
after this, the extracranial vessels dilate and pulsate in associ-
ation with local tenderness and the classical unilateral headache,
although it is unclear whether this or a neuronal abnormality
(‘spreading cortical depression’) is the cause of the symptoms.
5-Hydroxytryptamine (5HT, serotonin) is strongly impli-
cated, but this longstanding hypothesis remains unproven. 5HT
is a potent vasoconstrictor of extracranial vessels in humans and
also has vasodilator actions in some vascular beds. Excretion of
5-HIAA (the main urinary metabolite of 5HT) is increased fol-
lowing a migraine attack, and blood 5HT (reflecting platelet 5HT
content) is reduced, suggesting that platelet activation and 5HT
release may occur during an attack. This could contribute to
vasoconstriction during the aura and either summate with or
oppose the effects of kinins, prostaglandins and histamine to
cause pain in the affected arteries. The initial stimulus for
platelet 5HT release is unknown.
Ingestion by a migraine sufferer of vasoactive amines in food
may cause inappropriate responses of intra- and extracranial
vessels. Several other idiosyncratic precipitating factors are rec-
ognized anecdotally, although in some cases (e.g. precipitation
by chocolate), they are not easily demonstrated scientifically.
These include physical trauma, local pain from sinuses, cervical
spondylosis, sleep (too much or too little), ingestion of tyramine-
containing foods such as cheese, alcoholic beverages (especially
brandy), allergy (e.g. to wheat, eggs or fish), stress, hormonal
changes (e.g. during the menstrual cycle and pregnancy, and at
menarche or menopause), fasting and hypoglycaemia.
Some of the most effective prophylactic drugs against
migraine inhibit 5HT reuptake by platelets and other cells.
Several of these have additional antihistamine and anti-5HT
activity. Assessment of drug efficacy in migraine is bedevilled by
variability in the frequency and severity of attacks both within an
individual and between different sufferers. A scheme for the
acute treatment and for the prophylaxis of migraine, as well as
the types of medication used for each, is shown in Figure 23.1.

DRUGS USED FOR THE ACUTE MIGRAINE

AT TAC K

In the majority of patients with migraine, the combination of a

mild analgesic with an anti-emetic and, if possible, a period of

rest aborts the acute attack. 5HT1Dagonists (see below) can also

be used and have largely replaced ergotaminein this context

(although ergot-containing preparations are still available), due

to better tolerability and side-effect profile. They are very useful

in relieving migraine which is resistant to simple therapy.

SIMPLE ANALGESICS

Aspirin, 900 mg, or paracetamol, 1 g, are useful in the treat-

ment of headache. They are inexpensive and are effective in up

to 75% of patients. Other NSAIDs (see Chapter 26) can also be

used. During a migraine attack, gastric stasis occurs and this

impairs drug absorption. If necessary, analgesics should be

used with metoclopramide(as an anti-emetic and to enhance

gastric emptying).

ANTI-EMETICS FOR MIGRAINE

Metoclopramide, a dopamine and weak 5HT 4 antagonist, or

domperidone, a dopamine antagonist that does not penetrate

the blood–brain barrier, are appropriate choices. Sedative anti-

emetics (e.g. antihistamines, phenothiazines) should generally

be avoided. Metoclopramideshould be used with caution in

adolescents and women in their twenties because of the risk of

spasmodic torticollis and dystonia (see Chapter 21).

5HT 1 AGONISTS

The 5HT 1 agonists (otherwise known as ‘triptans’) stimulate

5HT1B/1D receptors, which are found predominantly in the

cranial circulation, thereby causing vasoconstriction predom-

inantly of the carotids; they are very effective in the treatment of

an acute migraine attack. Examples are rizatriptan,sumatriptan