Migraine 1

Outline Migraine

PathophysiologyTheories

Vascular theoryNeurogenic theoryNeurovascular theory

Newer targets and drugs

Pathophysiology of Migraine

TGVS=trigeminal vascular sensitization.Adapted from Pietrobon D, Striessnig J. Nat Rev Neurosci. 2003;4:386-398.

VasodilationNeurogenic

Inflammation

HeadachePain

Abnormal cortical activity

Hyperexcitable brain (Ca++, Glu, Mg++)

Cortical Spreading Depression

Activation/Sensitization of TGVS

Abnormal brain stem function

Excitation of brain stem, PAG, etc.

Central Sensitization


Proposed Mechanisms of Migraine Headache


Migraine Mechanisms

Iadecola C. Nature Medicine. 2002;8:111-112.

Aura Phase

Spasm of Cerebral Arteries

Headache Phase

Vasodilation of Cerebral Arteries

Wolf HG. Headache and Other Head Pain. 1963.


Classic Vascular Theory of Migraine

CBF=cerebral blood flow.Laurizen M. Brain. 1994;118:199-210.


Blood Flow During Aura and Headache Phase

NeuropeptideRelease

CentralSensitization

Pain SignalTransmission

Vasodilatation

Hargreaves RJ, Shepheard SL. Can J Neurol Sci. 1999;26(suppl 3):S12-S19.


Trigeminovascular Migraine Pain Pathways

Preventive medication target

Acute medication target

Pathophysiology of migraine

Vascular theory-attributes the phenomenon of vasodilatation.

Neurogenic theory- neuronal events, cortical spreading depression.

Third theory - accommodate vascular modifications with neuronal dysfunction.

Vascular theory

Harold G Wolff first one to explain

Vasoconstriction and ischemia accounts for symptoms of migraine aura,

Reactive vasodilatation activate primary sensory neurons.

Therapies provides evidence for this theory.

Cortical spreading depression

NMDA receptors involved in the genesis and propagation of CSD. CSD was blocked by NMDA receptors antagonists in various experimental models

Long lasting depression of neuronal activity.

Wave of oligemia begins in occipital cortex and spreads forward at rate of 2-3 mm/min

– Begins with aura and persists for hours after headache

– CBF changes not in distribution of any cerebral artery

– Consistent with primary neuronal event producing secondary vascular changes

James MF et al. J Physiol. 1999;519:415-425.


Cortical Spreading Depression

Hadjikhani N et al. Proc Natl Acad Sci USA. 2001;98:4687-4692.


Imaging of Cortical Spreading Depression (CSD)

The key pathway for pain in migraine is the trigeminovascular input from the meningeal vessels, which passes through the trigeminal ganglion and synapses on second-order neurons in the trigeminocervical complex (TCC).

These neurons in turn project in the quintothalamic tract and, after decussating in the brainstem, synapse on neurons in the thalamus.

Important modulation of the trigeminovascular nociceptive input comes from the dorsal raphe nucleus, locus coeruleus, and nucleus raphe magnus

perivascular trigeminal and parasympathetic nerve activation, release of vasodilator mediators, CGRP, neurokinen A, substance P

(pain signal)trigeminal ganglion trigeminal nucleus caudalis trigeminocervical complex

Brain stem aminergic nuclei can modify trigeminal pain processing

PET demonstrates brain stem activation in spontaneous migraine attacks

Brain stem activation persists after successful headache treatment

Brain stem: generator or modulator?

PET=positron emission tomography.Weiller C et al. Nat Med. 1995;1:658-660.


Brain Stem Involvement in Migraine

Pharmacological treatment of migraine includes

Acute (abortive) treatment

Preventive (prophylaxis) treatment

Preventive medication

NEWER DRUGS

Recent findings

CGRP is widely distributed in the nervous system, particularly at anatomical areas thought to be involvedwith migraine, including the trigeminovascular nociceptive system.

In studies, CGRP has been shown to be released during severe migraine attacks, and effective triptan treatment of an attack normalizes these levels.

CGRP administration triggers migraine in patients and CGRP receptor antagonists can abort migraine.

Moreover, recent data demonstrate that CGRP mechanism blockade either by small molecule receptor antagonists or by monoclonal antibodies can have a preventive effect in migraine.

Immunocytochemistry studies have shown that up to half of the trigeminal neurons produce CGRP within the trigeminal system, at various sites including the trigeminal ganglion, nerve endings and in higher order neurons and glia

. Centrally, CGRP is therefore involved in nociceptive transmission through second and third order neurons, and pain modulation in the brainstem, whereas peripherally it mediates vasodilatation through smooth muscle receptors

Although animal studies have shown the role of several neuropeptides during trigeminovascular system activation, including substance P, vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase activating peptide (PACAP)

only CGRP and PACAP seem to be released when durovascular structures are stimulated in the cat and in humans. CGRP and PACAP, but not substance P, are elevated in the cranial circulation during acute migraine attacks

These elevated levels normalize after effective triptan treatment of the migraine attack

CALCITONIN GENE-RELATED PEPTIDE ASA TREATMENT TARGET IN MIGRAINE

CGRP may have a role in mediating some of the varied painful and non-painful symptomatology of migraine attacks. Additionally, CGRP-targeted therapies do not seem to have the coronary vasoconstricting side-effects that triptans doSix small molecule CGRP receptor antagonists have been developed and five of them have demonstrated clinical efficacy in acute migraine. This class of drugs has acquired the stem name the gepants.

CGRP antagonist-BIBN4096BS(olcegapant)

CGRP mediates dilation of cerebral vasculature and increases in cerebral blood flow.

CGRP-induced vasodilation can activate nociceptors on cerebral vessels.

In humans, intravenous human CGRP administration induces migraine-like headache in susceptible migraineurs

The gepants

A summary of these agents is detailed in Table for clarity.

Two compounds, telcagepant and MK-3207 have been discontinued due to hepatotoxic side-effects,

olcegepant has been discontinuedasanoral formulation was too difficult to develop

whereas two compounds B144370A and BMS- 927711 showed clinical efficacy in phase II studies MK-1602 has no reported data as yet

compound Treatment class Clinical phase

Telcagepant [MK0974)-

CGRP receptor antagonist Phase 111

Olcegepant [BIBN4096BS)- CGRP receptor antagonist phase II

B144370- CGRP receptor antagonist phase II

Lasmiditan 5-HT 1F receptor agonist Phase 111

Tezampanel (LY-293558) AMPA and kainate receptor antagonist phase 111

Newer targets and drugs

Non-triptan 5-HT1 agonist, 5-HT1D agonists (PNU-109291 and

PNU- 142633) are potent inhibitors of dural plasma protein extravasation (PPE)

LY334370, which is a selective 5-HT1F agonist, inhibits single cell firing in the trigeminal nucleus caudalis (TNC)

Nitric oxide synthase inhibitor

An intravenous infusion of nitroglycerin (NTG) releases NO, causes migraine in more than 60% of migraineurs , and activates trigeminal neurons in experimental animals.

In a small RCT, 546C88, a non-selective NOS inhibitor, was administered intravenoulsy to migraineurs during an acute attack (Lassen et al., 1998). The 2-hr headache response rate was 67% (10/15) on 546C88 versus 14% (2/14) on placebo

Migraine 1

Health & Medicine

Transcript of Migraine 1