Professor Anthony DickensonUniversity College London, UK

HQ/FRE/19/0129. Date of preparation: June 2019

Migraine Pathophysiology & New Pathophysiology Based Preventive Treatment Options.

Disclosures

In the past two years:

• Speaker: Teva, Grunenthal, Allergan, Janssen, Novartis

• Advisory boards: Regeneron, Sandoz, Teva

CGRP discovery – heralding a new era of migraine prevention

1. Arkless K, et al. Handbook of Experimental Pharmacology, 2018.2. Humphrey PPA. J Head Face Pain 2008;48:685–7.

CGRP, calcitonin gene-related peptide; CVD, cardiovascular; mAb, monoclonal antibody

• For acute attacks; effective in just ~70%• Associated with side effects• Contraindicated in CVD

Anti-CGRP monoclonal antibodies are the first drugs developed specifically for migraine prevention

Last major advance in migraine: triptans introduced2

1982 1993 2018 Today

CGRP shown to play a key role in

migraine pain1

First anti-CGRP mAb available for migraine prevention

Three anti-CGRP mAbs available; one in development

CGRP discovered1

1990s

Cortex – where and how much pain

Peripheral eventsTissue and nerve damage

Spinal events

Brain stem descending controls

Limbic areas – unpleasantness Central reward and co-morbidities

Peripheral channels and sensorsPeripheral sensitization

Wind-upImpact of the brainCentral sensitization

Key types of pain

Nociceptive painPain caused by

an inflammatory ornon-inflammatory

response to anoxious stimulus

Tissue damage

Chemical activation

Osteoarthritis

Neuropathic painPain initiated or causedby a primary lesion or

disease in theperipheral or central

nervous system

Nerve damage

Ion channel changes

Both types of pain

can co-exist

Post-surgical pains

Low back pain, cancer pain etcNociplastic

All pains are not the same…..

Migraine

Central and peripheral mechanisms

Akerman S, et al. Pharmacol Ther 2017;172:151–70.CSD, cortical spreading depression; LC, locus coeruleus; PAG, periaqueductal gray; RVM, rostral ventromedial medulla;

SPG, sphenopalatine ganglion; TCC, trigeminocervical complex; TG, trigeminal ganglion

CGRP

The Search for the Holy Grail?

NSAIDs

LidoGBP

Nociceptive painChemical activation

Neuropathic painElectrical events

But git actions, low ceiling

Topical, central side effects

CGRP

CortexLocation and

intensity

Limbic brainAffective aspects

of painFear, anxiety,

sleep

Spinal cordIntegrates, amplifies and modifiesincoming messages Output to brain

Incoming peripheral nerves• Convey touch, temperature• Convey painful messages - heat, mechanical, chemical• Are altered by tissue and nerve damage

Descending controlsAllow top-down processesto enhance pain - link mood, sleep and pain

CGRP

ongoing painevoked pains

Allodynia – central sensitisation

Speaker’s own material

A-beta fibres – tactile sensations C and A-delta fibres – nociceptors – heat, mechanical and chemicals

CGRP: A key transmitter at both ends of pain fibres

Usoskin D, et al. Nat Neurosci 2015;18;145–53.Todd AJ. Nat Rev Neurosci 2010;11:823–36.

CGRP found in 46% C – fibres, 33% of A-delta fibres

O'Neill J, Brock C, Olesen AE, Andresen T, Nilsson M, Dickenson AH.Pharmacol Rev. 2012 Oct;64(4):939-71

Image adapted from Edvinsson L, et al. Nat Rev Neurol. 2018;14(6):338–350.

Peripheral release of CGRP can be monitored…in migraine and induced by triggersrs

Image adapted from Cady RK, et al. Headache. 2009;49(9):1258–1266.  Image adapted from Fanciullacci M, et al. Brain. 1997;120(Pt 2):283–288. 

NO and CGRP

Headache 52(9):1411-27 Messlinger K1, Lennerz JK, Eberhardt M, Fischer MJ.

CGRP and NO actions talk to each other

And does vasodilatation activate mechano pain receptors?

Release and /or changes in CGRP

• Whiplash – x 5 elevation of CGRP in plasma• Burn pain – increased CGRP levels in skin• CRPS – role in inflammation but not pain

• Severe Back Pain - + CGRP fibre innervation of disc• Pelvic pain – increased CGRP in neurites • Endometriosis - increased CGRP in neurites

Ebbinghaus, et al. (2015). Interleukin‐6‐dependent influence of nociceptive sensory neurons on antigen‐induced 

arthritis. Arthritis Research & Therapy. 17. 10.1186/s13075‐015‐0858‐0.

Expression of calcitonin gene-related peptide in the infrapatellar fat pad in knee osteoarthritis patientsJun Aikawa, et al.Journal of Orthopaedic Surgery and Research. 201712:65

CGRP is likely important in other pain states ‐ central and peripheral actions but accessible? 

Role of CGRP in peripheral and central pain mechanisms

Copyright © 2018 International Association for the Study of PainIyengar S, et al. Pain 2017;158:543–59.

AC, adenylyl cyclase; AMPA, amino-3-hydroxyl-5-methylsoxazole-4-propionic acid; cAMP, cyclic adenosine monophosphate; CREB, cAMP response element binding; NGF, nerve growth factor; NMDA, N-methyl-D-aspartate;

NOS, nitric oxide synthase; pERK, phosphorylated extracellular signal-regulated kinase; PGE2, prostaglandin E2; PK, protein kinase

PERIPHERAL SENSITISATION CENTRAL SENSITISATION

Peripheral sensitisation: contribution to the pathophysiology of chronic migraine

Reduced threshold for stimulation of the peripheral sensory neurons1

1. Dodick D, Silberstein S. Headache 2006;46(Suppl 4):S182–91.2. Strassman AM, et al. Nature 1996;384:560–4.3. Schlereth T, Birklein F. Neuromolecular Med 2008;10:141–7.

The peripheral processes are very differentCentral controls more common

Result: sensitisation of nociceptive neurons3

Release of neurotransmitters such as CGRP within the periphery can amplify and sustain the inflammatory response

May be due to chemical irritation of peripheral trigeminal fibres byinflammatory mediators1,2

CGRPα-GFP+ DRG neurons respond to agonists that evoke pain and itch sensationReleased from C-fibres activate A-delta fibres

McCoy ES, et al. PLOS ONE 2012;7(5): e36355. DRG, dorsal root ganglion; GFP, green fluorescent protein;

PrimaryThermal and mechanical

PeripheralSecondaryMechanicalNot peripheral spreadCENTRAL

Secondary - Mechanical hypersensitivity - increased area of response….

CGRP axons terminate in dorsal spinal / trigeminal cord

McCoy ES, et al. PLOS ONE 2012;7(5): e36355.

J Neurosci. 2017 Nov 1; 37(44): 10587–10596.Fremanezumab—A Humanized Monoclonal Anti-CGRP Antibody—Inhibits Thinly Myelinated (Aδ) But Not Unmyelinated (C) Meningeal NociceptorsAgustin Melo-Carrillo,1,2 Andrew M. Strassman,1,2 Rony-Reuven Nir,1,2 Aaron J. Schain,1,2 Rodrigo Noseda,1,2Jennifer Stratton,3 and Rami Burstein 1,2

A-delta fibres play a major role inmechanical pain

Wind‐up ‐ temporal summationLong‐term potentiation

Peripheral and descending pathways converge …

Spinal mechanisms -central hypersensitivity

++++++Early A – delta/C‐fibre inputs

Subsequent inputs

Altered pain states

Tactile, cold

Central sensitization

Enhanced responses to low and highthreshold stimuli - increased receptive fieldswithin nerve territory or area of damage

Can be induced in healthy volunteersby acute intense peripheral stimulation

Is seen in patients with peripheralneuropathy and OA

Stimulus no.1 6 12 16

Increased excitability

Iannetti et alPNAS 2006

Spinal mechanisms of central hypersensitivity spread upwards and change the brain

Edvinsson L, et al. Nat Rev Neurol 2018;14:338–50. CALCRL, calcitonin receptor-like receptor; RAMP, receptor activity modifying protein; RCP, receptor component protein

Stopping pain where it starts………

Peripheral release of CGRP

Acts on its receptor on vascular smooth muscle DILATION

Release from C-fibres –receptor on A-delta fibres PAIN

Edvinsson L, et al. Nat Rev Neurol 2018;14:338–50.

CGRP and pain; targets in migraine

Gray A. The Pharmaceutical Journal. 2016. Russell FA, et al. Physiol Rev. 2014;4:1099–142.

Don’t forget the ganglion…

BDNF, brain-derived neurotrophic factor; GABA, gamma-aminobutyric acid; mGluR, metabotropic glutamate receptor; SC, Schwann cellsMesslinger K. J Headache Pain 2018;19:22

Edvinsson L, et al. Nat Rev Neurol 2018;14:338–50

CNS

Spinal trigeminal nucleus

Dorsal horn of spinal cord at

C1 and C2

CNS

Dorsal pons Hypothalamus

Thalamus

Initiation

Headache phaseTrigeminal ganglion acts as

migraine pain amplifier

Trigeminal ganglion

CGRP circuitsActivation of

trigeminal ganglion• Gepants• Anti-CGRP antibodies• Anti-CGRP receptor

antibodies

Activation of trigeminovascularpain pathway

Ascending CNS pain pathways

Headachepain

Blood–brainbarrier

Pain needs a peripheral drive for central processing

• Pain is a sensory and emotional response

• Spinal – thalamic – cortical pathways –sensory

• Spinal – limbic brain projections – affective

• Anxiety and psychosocial issues in chronic pain

• Huge limbic input through LPb

• The brain is driven by the periphery but has a major impact on peripheral inputs

CVLM, caudal ventrolateral medulla; LPb, lateral paracore bundle; NTS, nucleus tractus solitaries; PAG, periaqueductal greyImages adapted from Todd AJ., Nat Rev Neurosci 2010;11:823–836. Text refers to the Speaker’s own opinion.

Baron R. et al, Ann Neurol 2013;74:630–36

Peripheral input drives central sensitisationand changes descending controls

Two main ascending pathwaysSensory and affective

The brain needs to know about peripheral inputs – sensory and affective pathwaysCancer-induced anorexia and malaise are mediated by CGRP neurons in the parabrachial nucleus

Spino-thalamic tract for intensity and location – cortexParabrachial inputs into the limbic brain – fear, aversion etc: Nature Reviews Neuroscience volume14, pages502–511 (2013) J Clin Invest DOI: 10.1172/JCI43498 Nature Neuroscience 20(7) · June

Limbic SystemAmygdala

Hypothalamus

Periaqueductal grey PAG

Rostroventral medial medulla RVM

Mood, fear, anxiety, ragepanic, sleep-wake….

Locus coeruleus

On-CellOff-Cell

Neutral Cell

Inhibitory controls excitatory controls

Noradrenaline 5HT

Noradrenaline and 5-HT AND THE CONTROL OF PAIN

PAIN

Alpha-2 adrenoceptor

Same circuitsimaged in humans

Descending inhibitions Descending excitationsCHANGED IN PERSISTENT PAINS

Protects Promotes

NA

Noradrenaline 5-HT

Alpha2 AR 5HT2/3R

One pain inhibits anotherDiffuse Noxious Inhibitory ControlsConditioned pain modulation

Through descending inhibitions

A marker for intrinsic pain modulation

Strong CPM - less pain after exerciseNormal CPM - 94% of the healthy populationReduced CPM - predicts chronic post-surgical painReduced CPM - patients with migraine, tissue and nerve damage

Anterior cingulate Left CE amygdalakappa opioid

medial prefrontal cortex

dorsal reticular nucleusopioid

Locus coeruleus RVM

Diffuse Noxious Inhibitory ControlsConditioned Pain Modulation

NA 5HT

- +

Parabrachialnucleus

Spinal cordLamina ISpinal cord

Lamina VAlpha-2 R 5HT3R

PAG

Image adapted from Mainero C, et al. Ann Neurol. 2011;70(5):838–45. Image adapted from Benarroch EE. Neurology. 2011;77(3):281–287.

Migraine changes the brain…….

Encoding of danger by parabrachial CGRP neurons

C A Campos et al. Nature 555, 617–622 (2018) doi:10.1038/nature25511

Rapid control of CGRPPBN neurons before and during painful stimuli – and touch and feeding…and are part of recall of a pain memory….

Does the brain talk to the periphery? And how??

Progress in Neurology and PsychiatryAnti-CGRP monoclonal antibodies: breakthrough in migraine therapeuticsRATNA KRISHNASWAMY, BILAL HAIDER MALIK, SAFEERA KHAN, DEEPTI GUPTA, MUHAMMAD ISLAM, SHRAWAN KUMAR MANDAL, IAN H RUTKOFSKY AUGUST 7, 2019 VOLUME 23.03 JULY-SEPTEMBER 2019

Images adapted from Akerman S, et al. Pharmacol Ther. 2017;172:151–170.

Central and peripheral mechanisms

CGRP

Causes dilatation – activation of mechanosensitive pain receptors?Released from C- fibres – activates A- delta fibresPeripheral sensitization – drives danger systemsFavours central sensitization – meets a changed CNS – more pain -facial allodynia

Altered central processingCentral sensitization from withinFailed descending inhibitions

PERIPHERAL AND CENTRAL PROCESSINGIS THERE CROSS-TALK??

• Multiple studies have confirmed that release of calcitonin gene-related peptide (CGRP) is increased during acute migraine attacks.

• In the trigeminal ganglion, CGRP is expressed in C-fibres and its receptor is expressed in Aδ-fibres; these types of fibres are involved in different aspects of pain perception.

• The trigeminal ganglion is central to the trigeminovascular reflex, which is triggered to protect against vasoconstriction; triggering of this system in patients with migraine leads to the perception of pain.

• The trigeminal ganglion and dura are not behind the blood–brain barrier; therefore, they are likely to be the targets of gepants and antibodies in migraine treatment.

• In clinical trials, CGRP receptor antagonists, anti-CGRP antibodies and anti-CGRP receptor antibodies were efficacious in migraine prophylaxis, supporting a role for CGRP in migraine pathophysiology.Edvinsson L, et al. Nat Rev Neurol. 2018;14(6):338–350.