A-Textbook-of-Clinical-Pharmacology-and-Therapeutics-5th-edition
A-Textbook-of-Clinical-Pharmacology-and-Therapeutics-5th-edition
A-Textbook-of-Clinical-Pharmacology-and-Therapeutics-5th-edition
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CHAPTER 23<br />
MIGRAINE<br />
● Pathophysiology 142<br />
● Drugs used for the acute migraine attack 142<br />
● Drugs used for migraine prophylaxis 143<br />
PATHOPHYSIOLOGY<br />
Migraine is common <strong>and</strong> prostrating, yet its pathophysiology<br />
remains poorly understood. The aura is associated with intracranial<br />
vasoconstriction <strong>and</strong> localized cerebral ischaemia. Shortly<br />
after this, the extracranial vessels dilate <strong>and</strong> pulsate in association<br />
with local tenderness <strong>and</strong> the classical unilateral headache,<br />
although it is unclear whether this or a neuronal abnormality<br />
(‘spreading cortical depression’) is the cause <strong>of</strong> the symptoms.<br />
5-Hydroxytryptamine (5HT, serotonin) is strongly implicated,<br />
but this longst<strong>and</strong>ing hypothesis remains unproven. 5HT<br />
is a potent vasoconstrictor <strong>of</strong> extracranial vessels in humans <strong>and</strong><br />
also has vasodilator actions in some vascular beds. Excretion <strong>of</strong><br />
5-HIAA (the main urinary metabolite <strong>of</strong> 5HT) is increased following<br />
a migraine attack, <strong>and</strong> blood 5HT (reflecting platelet 5HT<br />
content) is reduced, suggesting that platelet activation <strong>and</strong> 5HT<br />
release may occur during an attack. This could contribute to<br />
vasoconstriction during the aura <strong>and</strong> either summate with or<br />
oppose the effects <strong>of</strong> kinins, prostagl<strong>and</strong>ins <strong>and</strong> histamine to<br />
cause pain in the affected arteries. The initial stimulus for<br />
platelet 5HT release is unknown.<br />
Ingestion by a migraine sufferer <strong>of</strong> vasoactive amines in food<br />
may cause inappropriate responses <strong>of</strong> intra- <strong>and</strong> extracranial<br />
vessels. Several other idiosyncratic precipitating factors are recognized<br />
anecdotally, although in some cases (e.g. precipitation<br />
by chocolate), they are not easily demonstrated scientifically.<br />
These include physical trauma, local pain from sinuses, cervical<br />
spondylosis, sleep (too much or too little), ingestion <strong>of</strong> tyraminecontaining<br />
foods such as cheese, alcoholic beverages (especially<br />
br<strong>and</strong>y), allergy (e.g. to wheat, eggs or fish), stress, hormonal<br />
changes (e.g. during the menstrual cycle <strong>and</strong> pregnancy, <strong>and</strong> at<br />
menarche or menopause), fasting <strong>and</strong> hypoglycaemia.<br />
Some <strong>of</strong> the most effective prophylactic drugs against<br />
migraine inhibit 5HT reuptake by platelets <strong>and</strong> other cells.<br />
Several <strong>of</strong> these have additional antihistamine <strong>and</strong> anti-5HT<br />
activity. Assessment <strong>of</strong> drug efficacy in migraine is bedevilled by<br />
variability in the frequency <strong>and</strong> severity <strong>of</strong> attacks both within an<br />
individual <strong>and</strong> between different sufferers. A scheme for the<br />
acute treatment <strong>and</strong> for the prophylaxis <strong>of</strong> migraine, as well as<br />
the types <strong>of</strong> medication used for each, is shown in Figure 23.1.<br />
DRUGS USED FOR THE ACUTE MIGRAINE<br />
ATTACK<br />
In the majority <strong>of</strong> patients with migraine, the combination <strong>of</strong> a<br />
mild analgesic with an anti-emetic <strong>and</strong>, if possible, a period <strong>of</strong><br />
rest aborts the acute attack. 5HT 1D agonists (see below) can also<br />
be used <strong>and</strong> have largely replaced ergotamine in this context<br />
(although ergot-containing preparations are still available), due<br />
to better tolerability <strong>and</strong> side-effect pr<strong>of</strong>ile. They are very useful<br />
in relieving migraine which is resistant to simple therapy.<br />
SIMPLE ANALGESICS<br />
Aspirin, 900 mg, or paracetamol, 1 g, are useful in the treatment<br />
<strong>of</strong> headache. They are inexpensive <strong>and</strong> are effective in up<br />
to 75% <strong>of</strong> patients. Other NSAIDs (see Chapter 26) can also be<br />
used. During a migraine attack, gastric stasis occurs <strong>and</strong> this<br />
impairs drug absorption. If necessary, analgesics should be<br />
used with metoclopramide (as an anti-emetic <strong>and</strong> to enhance<br />
gastric emptying).<br />
ANTI-EMETICS FOR MIGRAINE<br />
Metoclopramide, a dopamine <strong>and</strong> weak 5HT 4 antagonist, or<br />
domperidone, a dopamine antagonist that does not penetrate<br />
the blood–brain barrier, are appropriate choices. Sedative antiemetics<br />
(e.g. antihistamines, phenothiazines) should generally<br />
be avoided. Metoclopramide should be used with caution in<br />
adolescents <strong>and</strong> women in their twenties because <strong>of</strong> the risk <strong>of</strong><br />
spasmodic torticollis <strong>and</strong> dystonia (see Chapter 21).<br />
5HT 1 AGONISTS<br />
The 5HT 1 agonists (otherwise known as ‘triptans’) stimulate<br />
5HT 1B/1D receptors, which are found predominantly in the<br />
cranial circulation, thereby causing vasoconstriction predominantly<br />
<strong>of</strong> the carotids; they are very effective in the treatment <strong>of</strong><br />
an acute migraine attack. Examples are rizatriptan, sumatriptan