New Ideas for Migraine Treatment

Question 1

naratriptan vs alniditan

Answer 1

naratriptan (5HT1B/1D/1F) - 60% inhibition
alniditan (5HT1B/1D) - no effect at all
blocking 1B/D = response
blocking both = lesser effect (1F agonist)

Question 2

IF subunit block

Answer 2

IF not on blood vessels therefore no contraindications (nerves only)

Question 3

Lasmiditan (Reyvoy)

Answer 3

stronger than naratriptan
improves fatigue (most bothersome symptom) 44% improvement at 100mg
5HT1F agonist - risk of medication overuse & hypersensitivity (like triptans)
stimulate meninges in rats and trigeminal nerve - place electrode in SC (Vila-Pueyo et al., 2022)

Question 4

what is a risk with lasmiditan

Answer 4

more CGRP in SC with 1F agonist
side effects of CGRP: vertigo (cross BBB 15%) paresthesia (9%) somnolence (7%) fatigue (6%) all due to central penetrance
higher than normal drink-drive limit

Question 5

CGRP

Answer 5

neuropeptide from the calcitonin family
a-CGRP = in brain
B-CGRP = in enteric NS side effects: diarrhoea/constipation
-vasodilator -pain neurotransmission

Question 6

CGRP signalling

Answer 6

CRLR = calcitonin like receptor
CRLR works with RAMP (receptor activity modifying protein)
swap RAMP for RAMP2/3 = forms AM1/2 receptor

Question 7

patients with severe migraines

Answer 7

blood obtained from jugular vein
increases CGRP
after stimulation = CGRP and PACAP released, no substance P

Question 8

sensory nerves

Answer 8

trigeminal ganglion (TG) - express CGRP/SP/NKA/PACAP
Sphenopalative ganglion (SPG) - PACAP/AChE/VIP
superior cervical ganglion (SCG)

Question 9

substance P

Answer 9

failed to show efficacy in humans and animals

Question 10

CGRP infusion

Answer 10

Hansen et al., 2010
28% experienced aura following CGRP infusion (triggers migraine in patients)

Question 11

action of triptans

Answer 11

triptans (sumatriptans) normalise CGRP levels by preventing release
CGRP receptor on blood vessels and SC
5HT1B/D is the triptan receptor

Question 12

CGRP receptor antagonist

Answer 12

BIBN - trigeminocervical complex (SC)
glutamate produces spikes/CGRP dampens response - less effective in thalamus

Question 13

periaqueductal grey PAG

Answer 13

inject drug into PAG
CGRP sensitised animals
BIBN/CGRP (8-37) antagonist decreases pain processing

Question 14

olcegepant

Answer 14

CGRP antagonist
no withdrawal in medication overuse headache vs sumatriptan
2-5mg 66% vs placebo 25%
limitation: available as IV, another epant=liver toxicity

Question 15

monoclonal antibodies (prevention)

Answer 15

zumab = humanised umabs = human (reduces immunogenicity)
adv: large molecular weight (~150Da)/long serum t1/2(~30days)/high potency/reduced off-target toxicity
dis: cannot cross BBB(only 0.1% cross)/birth defects?/injection IV/IP/immunogenicity/expensive

Question 16

when can monoclonal antibodies be prescribed according to NICE

Answer 16

fail 3 preventatives
1 has to be botox

Question 17

4 approved umabs

Answer 17

erenumab (CGRP R) - fatigue/headache (3-4 day change vs placebo 1)
fremanezumab (CGRP) - injection site pain/pruritis
galcanezumab (CGRP) - injection site pain/abdominal pain/Upper RTI
eptinezumab (CGRP) - RTI/UTI/fatigue/nausea

Question 18

antibody binding

Answer 18

antibodies bind to CGRP ligand
block RAMP
no effect on efficacy