Migraines

Question 1

what is primary headaches?
what does primary headache include ?

Answer 1

• primary headache are headaches not caused by another medical condition

primary headache include :
-migraine
-tension- type headache
-cluster headache
-other primary headache

Question 2

what is secondary headache

Answer 2

Secondary headaches are caused by problems elsewhere

Question 3

what is episodic migraine?

Answer 3

occurs on less than 15 days per month and can be further subdivided into low frequency (1-9 per month) and high frequency (10-14 days per month)

Question 4

what is chronic migraine

Answer 4

occurs on 15 or more days per month

Question 5

what is two major sub-types for migrane

Answer 5

• migraine without aura
  -migraine with aura

migraine without aura
-most common
-higher attack frequency
-usually more debiliating

migraines with aura
-headaches classed as for without aura
-additional visual and/or sensory disturbances

Question 6

what is the Diagnostic Criteria: Migraine

Answer 6

> 5 headache attacks lasting between 4-72 hours

Headache must have at least two of the following characteristics
- Unilateral location
- Pulsating quality
- Moderate or severe pain intensity
- Aggravated by or causes avoidance of routine physical activity (e.g., walking or climbing stairs)

During headache at least one of the following
- Nausea and/or vomiting
- Photophobia and phonophobia

Headache not attributed to another disorder

Question 7

what are the Diagnostic Criteria: Migraine With Aura

Answer 7

At least two headache attacks (as characterized for without aura) lasting between 4-72 hours

Patients must have no motor weakness

the aura consists of :
- Fully reversible positive or negative visual symptoms e.g., flickering lights, spots or lines or loss of vision

• Fully reversible positive or negative sensory symptoms including positive features e.g., pins and needles or numbness
• Fully reversible dysphasic speech disturbance

Question 8

what is the complications of migraines?

Answer 8

1. Status migrainosus - >72 h attack
2. Migrainous infarction (stroke) - Aura >1 h, blood vessels narrow O2 drops
3. Persistent aura without infarction - Aura >1 week
4. Migraine aura-triggered seizure - Seizure follows a migraine

Question 9

What Triggers Migraine Attacks?

Answer 9

Migraine is an inherited tendency to headache and cannot be cured

Migraine can be modified and controlled by life-style adjustment and the use of medicines

triggers include:
chocolate
alcohol
caffeine
sleeping late

Question 10

what is migraine pathophysiology?

Answer 10

Migraine is a complex genetic disorder

Likely a polygenic multifactorial inheritance

Genome-wide association studies have identified potentially interesting genes

Present understanding derived from familial hemiplegic migraine (FHM): a rare monogenic, autosomal dominant form of migraine with aura

Three genes identified are either ion channels or transporters

(many genes involved so its hard to target)

Question 11

what is the Current Migraine Theory

Answer 11

Migraine is a neurovascular disease

Activation and sensitization of the trigeminovascular pain pathway

Innervates cranial tissues, in particular the meninges and their large blood vessels

A phenomenon called “Cortical Spreading Depression” is the neurophysical correlate of migraine aura

Cortical Spreading Depression is a slowly propagating wave of strong neuronal and glial depolarization

Question 12

what are common prescriptions for migraineurs

Answer 12

Used for : hypertension
beta blockers
calcium channel blockers

used for : Pain
norcotic analegesics - codiene

Used for : antidepressants
- Tricyclic antidepressants, monoamine oxidase inhibitors, Selective Serotonin Reuptake Inhibitors, Serotonin and Norepinephrine Reuptake Inhibitors (SNRIs

Used for : Discovered in 1920s; originally used to stop bleeding after a woman gave birth
- Ergots

used for antiwirnkle
botox

used for: A migraine drug! in 1990s
triptans

Currently very few drugs specifically for the treatment of migraine

Question 13

what is the first line acute treatments for migraine

Answer 13

Aspirin (900 mg): first-line treatment for patients with acute migraine.

Ibuprofen (400 mg): first-line treatment for patients with acute migraine. If ineffective, the dose should be increased to 600 mg.

Triptans: first-line treatment for patients with acute migraine. The first choice is sumatriptan (50–100 mg), but others should be offered if sumatriptan fails. (NOT used for longterm)

Combination therapy using sumatriptan (50–85 mg) and naproxen (500 mg).

Often prescribed with anti-emetics e.g., Metoclopramide (10 mg) or prochlorperazine (10 mg).

Question 14

what do triptans act on the targets ?

Answer 14

5-HT was first proposed to be involved in the pathophysiology of migraine as levels decrease during attacks

Slow intravenous infusions of 5-HT could abort a migraine attack

Lead to the discovery of “Triptans”: 5-HT1D/B/F receptor agonists
- e.g., Sumatriptan (1st generation)
-e.g., Zolmitriptan, Rizatriptan, Naratriptan (2nd generation)
have higher oral bioavailability and longer plasma half-life

Triptans are effective in approximately 70% patients

Do not prevent migraines-provide relief

Question 15

what is the mechanism of action of triptans?

Answer 15

Proposed mechanisms of action of triptans include:
- constriction of cranial arteries
-inhibitory actions on the CNS
- inhibition of presynaptic TG neurons

agonists of 5-HT

Question 16

what patients is triptans contraindicated in?

Answer 16

Contraindicated in patients with coronary or cardiovascular disease, hypertension or that are pregnant

Question 17

what can overuse of triptans do?

Answer 17

Overuse can cause severe rebound attacks-medication-overuse headaches - when they stop taking it

Question 18

what is the Migraine Medications: Prophylactic Treatment
how long do you have to suffer with migranes to start?

Answer 18

Considered for patients suffering 4+ attacks per month

Preventive medications aim to reduce the frequency, severity and length of migraines and may increase the effectiveness of symptom-relieving medicines used during migraine attacks

b-blockers e.g., propranolol (80-160 mg, daily): unclear how they work as they cause dilation of blood vessels

Topiramate (50-100 mg daily): blocks voltage-dependent sodium and calcium channels; mechanism of action for migraine unclear

Tricyclic anti-depressants e.g., amitriptyline, (25–150 mg at night),thought to work by preventing reuptake of 5-HT and antagonizing 5-HT2 receptors

Anti-convulsants e.g., sodium valproate (400–1500 mg daily); voltage-dependent sodium channels

Candesartan (16 mg daily); angiotensin II receptor antagonist

Botulinum toxin A is recommended for the prophylactic treatment of patients with chronic migraine where medication overuse has been addressed and patients have been appropriately treated with three or more oral migraine prophylactic treatments

Question 19

Molecular Mediators of Migraine: Calcitonin Gene-Related Peptide (CGRP) what is it?

Answer 19

CGRP is a multifunctional 37 amino acid neuropeptide; derived from alternative processing of the calcitonin gene

CGRP is a potent vasodilator and is involved in neurogenic inflammation and nociception

CGRP receptors are present at sites relevant to migraine - pheripheral and central

Injection of CGRP into migraineurs can cause delayed migraine-like headaches

Question 20

when does CGRP increase?

Answer 20

Increased levels of CGRP in serum and saliva of migraineurs during attacks

Question 21

CGRP Receptors as Molecular Targets for the Treatment of Migraine
what were the possible developments and their drawbacks

Answer 21

CGRP receptor antagonists the so-called “Gepants” have been promising in clinical trials

Olcegepant: first CGRP receptor antagonist to enter trials

Efficacious in Phase II clinical trials: i.v. only, poor oral availability

Telcagepant: reached Phase III trials before termination due to high liver transaminases

Additional drawbacks include short duration of effect

Question 22

in development stage:
Monoclonal Antibodies to Treat Migraine:
problems?

Answer 22

Monoclonal antibodies must be injected (intravenous or subcutaneous)

Must be humanized or fully human antibodies

Long-term consequences of injecting antibodies, unknown

Question 23

what are the current prophylactic treatment

Answer 23

No cure

Erenumab (Aimovig): CGRP Receptor
Galcanezumab (Emgality): CGRP
Fremanezumab (Ajovy): CGRP
Eptinezumab (Vyepti): CGRP

used for Episodic and chronic migraine (preventative only)

Question 24

Current Status: New Treatments

Answer 24

Gepants (CGRP receptor antagonists)
- Ubrogepant (Ubrelvy): The first-in-class oral CGRP antagonist; approved by FDA (December 2019)
-Rimegepant (Nurtec ODT): FDA & EU approved
- Atogepant: FDA approved Sep 2021 (episodic)
Gepants: No evidence for rebound headaches

Ditans (5-HT1F receptor agonists)
- Only affects nerves, not blood vessels
- Lasmiditan (Reyvow): FDA approved (October 2019)