Migraine

Dr. Edmeads

April 29, 2005

 

Acute attack and management

 

Hippocrates – first description of migraine w/ aura

Aretaeus of Cappadocia – first description of migrane w/o aura

Galen of Pergamum – “hemicrania

Thomas Willis – 1640 – associated migraine with distention of meningeal blood vessels

 

First rational pharmacologic treatment was ergot.

Toxic ingestion of ergotamines caused St. Anthony’s Fire (limb ischemia, occasional psychosis from LSD in the fungus).

Pure ergot first extracted in 1918 by Stoll.

Harold Wolff – 1938 – first identified temporal artery associations with migraine and relief with ergotamines.

 

Now we know that serotonin most involved in how ergot reacts to blood vessels. But dihydroergotamine also has DA and NE effects, causing N&V and vasoconstriction.

Triptans have same 5HT moiety, without the DA and NE moieties of dihydroergotamine.

 

Triptans have specific affinity for 5HT1b/d/f receptor, some effect on 5HT1a. More specific and also more effective than ergots.

 

Which triptan? 6 in Canada, 7 in US.

They’re all pretty much the same.

Rizatriptan 10, eletriptan 80, almotriptan 12.5 are better than sumatriptan at 2 hours pain free.

NNT=3 for sumatriptan, NNT= 2-9 for all triptans.

 

Contraindications:

-         coronary artery disease – 5HT1b receptors also on coronary arteries

-         ?uncontrolled hypertension (this group was excluded from the trials)

-         Hemiplegic or basilar migraine (theoretical risk)

-         Concurrent with other 5HT1b/d agonists

-         Other drugs e.g., MAO inhibitors with suma, zolmi, riza

 

Adverse events:

-         feeling of flushing, numbness, pressure, tingling

-         nausea, lethargy, dizziness (could be due to migraine)

-         chest pain in 2-3% of people ?not cardiac ?esophageal spasm

-         most people have no side effects

 

Need to take triptans ASAP, in adequate dose, appropriate route (not PO if nausea), and in e with other meds.

Not clear if triptans work with an aura, makes sense though.

Recurrence rate less with higher doses, not necessarily higher side effects.

 

Variable oral bioavailability, receptor binding affinity, membrane kinetics.

 

Wafers work same speed as tablets.

Nasal spray just as efficacious, slightly faster, good in nausea. (zomi, suma)

S/C inj faster and more effective. (sumatriptan 6mg)

 

Combinations:

-         triptan + NSAID

-         triptan + metoclopramide (absorption in small intestine)

-         triptan + antinausea agent

 

Pathophysiology of migraine

 

Hypersensitive cortex in migraineurs, seen in ABR and VEPs, photic drive in EEG.

Even migraine w/o aura involves a front of electrical excitability from occipital cortex forward. “Spreading depression” – a misnomer, brief excitation followed by depression at 3mm/min, ending in the frontal lobe. If adequately intense, causes aura (1 in 8 migraineurs). Wave of excitation affects the trigeminal nerve endings, stimulating release of NTs including CGRP, which dilates blood vessels via NO. Nitric oxide may also be involved in the spread. Plasma protein extravasation caused by substance P and neurokinin.

 

Presynaptic 5HT1d/(f) receptor on trigeminal nerve ending inhibits CGRP release. Blood vessel 5HT1b receptor constricts blood vessel. 5HT1d/f will also affect the brainstem synapses to inhibit the pain transmission. 5HT1d also inhibits plasma protein esxtravasation.

 

Nuclei of brainstem affect the cortex. It is believed that genetically, the brainstem nuclei make abnormal amounts of NTs (low 5HT). Comorbidities of depression, anxiety, and irritable bowel syndrome. Many believe migraines begin in the brainstem. Also comorbidity in childhood of paroxysmal vertigo and motion sickness.

 

5HT1d selective agonist not very effective, but can cause chest pain! 5HTf selective agonist is effective. Need to avoid 5HT1b vasoconstriction. Now working on CGRP and NO targets.

 

Other potential targets are DA and GABA, haven’t really been looked at.

 

Status migranosis

-         IV neuroleptic first – chlorpromazine, prochlorpromazine, metoclopramide

-         IV dihydroergotamine after IV neuroleptic – contraindicated in pregnancy

-         IV narcotic after antinausea agent

-         IM ketorolac

-         IV valproate or IV corticosteroid less strong evidence – category D for pregnancy

-         If seen in office PO prednisone 50mg/d x 5days (poor evidence, but clinically used)