Workshop 10 – Novel therapies for the treatment of episodic migraine.

Question 1

What are the current treatments for the prevention of episodic or chronic migraines?

Answer 1

• Propanolol 80-160mg daily
• Topirimate 50-100mg
• Amytriptyline 25-150mg at night
• Candesartan 16mg
• Botulinum toxin A when medication overuse has been adressed and patients have been appropriately treated with three or more oral migrain treatments

Question 2

What is the acute treatments for migraines?

Answer 2

• Aspirin 900mg
• Ibuprofen 400mg
• Triptans; first choise sumatriptan 50-100mg
• Combination using sumpitriptan 50-85mg and naproxen 500mg

Question 3

What is the Trigemino vascular hypothesis?

Answer 3

Theory that explains the underlying mechanism of migraines. The trigeminal nerve is responsible for transmitting sensory information from the face and head to the brain. When activated, the trigeminal nerve releases neuropeptides including substance P and CGRP, which can lead to neurogenic inflamation and pain sensitization. CGRP is thought to cause vasodilation of the blood vessels in the brain, and also lead to pain signals being transmitted to the brain which causes the throbbing, pulsating pain associated with migraines

Question 4

What are the advantages and disadvantages of using therapeutic mAbs?

Answer 4

Advantages:
- They have longer duration of action that allows for less frequent dosing and faster acting
- Antibodies are highly specific and can provide a more effective blockade than small molecule antagonists
- Low variability in production
- Do not penetrate into the brain unless the blood–brain barrier integrity damaged. Relevant to migraine: The meninges, epidural capillaries, and veins have no BBB.
- Antibodies are mostly eliminated by proteolytic degradation, not involving the liver and are not substrates for P450 cytochrome isoenzymes. Hence potential for hepatotoxicity and drug–drug interactions is reduced.

Disadvanatges:
- Due to their large dimensions, low permeability through cell membrnaes, and instability in the GI tract, as they are proteins, mABs must be administered parenterally
- Expensive to generate
- Do not penetrate into the brain unless the blood–brain barrier integrity damaged. Relevance for other CNS disorders.

Question 5

Why have CGRP receptor small molecule antagonists (gepants) been largely superseded?

Answer 5

• Gepants are designed for acute migraine treatment
• Appear to be effective in short term treatment
• Early studies terminated early due to abnormal liver function tests, hepatotoxicity following long term administartion
• Site of action thought not to be centrally mediated but do not cross the BBB, potential for side effects
• Evidence of poor oral bioavailability
• Side effects of orally bioavaialble gepants were fatigue, diarrhoea and influenza like symptoms

Question 6

What are ditans?

Answer 6

Selective 5-HT1F receptor antagonists acting directly on trigeminal nerves.
Unlike triptans which antagonise multiple serotonin receptors. But dizziness is an adverse effect