NEUROPHARMACOLOGY CLINICAL PEARLS: MIGRAINE ... NEUROPHARMACOLOGY CLINICAL PEARLS: MIGRAINE Stephen

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  • OU Neurology

    NEUROPHARMACOLOGY CLINICAL PEARLS: MIGRAINE

    Stephen M. Clayton, Jr., M.D. Assistant Professor

    Department of Neurology The University of Oklahoma Health Sciences Center

    OAPA 46th Annual CME Conference for Physician Assistants September 18-20, 2019

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    RELEVANT DISCLOSURE & RESOLUTION

    Under Accreditation Council for Continuing Medical Education guidelines disclosure must be made regarding relevant financial

    relationships with commercial interests within the last 12 months.

    Stephen M. Clayton, Jr., MD I have no relevant financial relationships or affiliations

    with commercial interests to disclose

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    EXPERIMENTAL OR OFF-LABEL DRUG/THERAPY/DEVICE DISCLOSURE

    I will be discussing experimental or off-label drugs, therapies and/or devices that have not been approved by the FDA.

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    NEUROPHARMACOLOGY CLINICAL PEARLS: MIGRAINE

    Learning Objectives Upon completion of this session, participants will improve their competence and performance by being able to:  Understand basic pathophysiology of migraine and explain these

    principles in lay terms  List various neurotransmitters (including small molecules and

    neuropeptides) and receptors involved in migraine pathophysiology

     Describe the major biochemical effect of drugs or drug classes commonly used to treat migraine and primary headache disorders

     Recognize chemical structural similarities of certain medications used to treat migraine, either between each other or with neurotransmitters

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    BASIC MIGRAINE PATHOPHYSIOLOGY

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    MIGRAINE PATHOPHYSIOLOGY What Is Migraine?  Genetic condition causing increased susceptibility to

    “attacks” of neuronal dysfunction leading to stereotyped spells often with a variety of systemic manifestations

     Attacks most often include:  Headache  Sensory phobias (light, sound, motion, temperature, smells)  Nausea +/- vomiting  ...but sometimes with “aura” = focal neurologic deficits

     Classically 4 phases: prodrome, aura, pain, postdrome Many cannot appreciate all 4 phases, but remember pain Many have multiple spell types  A single spell type may evolve throughout life

    Presenter Presentation Notes Goadsby PJ, Holland PR, Martins-Oliveira M, Hoffmann J, Schankin C, Akerman S. Pathophysiology of Migraine: A Disorder of Sensory Processing. Physiol Rev. 2017;97(2):553-622. Gordon DL. Headache and Migraine. Oct. 24, 2018 PowerPoint presentation to medical students at the University of Oklahoma College of Medicine.

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    MIGRAINE PATHOPHYSIOLOGY What Causes Migraine Attacks? Unclear initial biochemical event but several

    factors contributing to attacks: Wave of biochemical change at neuronal level =

    “cortical spreading depression” Changes within trigeminovascular system Increased sensitization of cortical neurons via

    thalamocortical projections Underlying genetics Environmental triggers (more on this later…)

    Presenter Presentation Notes Goadsby PJ, Holland PR, Martins-Oliveira M, Hoffmann J, Schankin C, Akerman S. Pathophysiology of Migraine: A Disorder of Sensory Processing. Physiol Rev. 2017;97(2):553-622.

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    MIGRAINE PATHOPHYSIOLOGY Cortical Spreading Depression (CSD)

    Intense depolarization/excitation spreading a few millimeters per minute, followed by prolonged disruption in appropriate

    signal conduction → “depression”

     Unclear why but likely ↓ membrane resistance due to opening of nonselective cation channels → ions move along concentration gradients  ↑ intracellular [Ca2+] and ↑ extracellular [K+]  Depolarization → ↑ extracellular glutamate (excitatory) → ↑ NMDA

    receptor activation (excitatory)

     Large metabolic demand on cell to attempt restoring homeostasis by repleting intracellular energy stores  ↓ ATP, O2, glucose, pH

    Presenter Presentation Notes Ayata C, Lauritzen M. Spreading Depression, Spreading Depolarizations, and the Cerebral Vasculature. Physiol Rev 95: 953–993, 2015. doi:10.1152/physrev.00027.2014.

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    from Ayata C and Lauritzen M, 2015

    20-HETE = 20-Hydroxyeicosatetraenoic acid (a metabolite of arachidonic acid); CGRP = calcitonin gene-related peptide; EDHF = endothelium-derived hyperpolarizing factor; EETs = epoxyeicosatrienoic acids (metabolites of arachidonic acid);

    NE = norepinephrine; NK-A = neurokinin A; NO = nitric oxide; NPY = neuropeptide Y; PACAP = pituitary adenylate cyclase activating peptide; SP = substance P; VIP = vasoactive intestinal peptide

    Presenter Presentation Notes Ayata C, Lauritzen M. Spreading Depression, Spreading Depolarizations, and the Cerebral Vasculature. Physiol Rev 95: 953–993, 2015. doi:10.1152/physrev.00027.2014.

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    MIGRAINE PATHOPHYSIOLOGY Thalamocortical Projections

    from Goadsby PJ, et al.

    Au = auditory cortex Ect = ectorhinal cortex

    Ins = insular cortex LC = locus coeruleus

    M1/M2 = primary and secondary motor cortex

    PAG = periaqueductal gray PtA = parietal association cortex

    RS = retrosplenial cortex RVM = rostral ventromedial medulla

    S1/S2 = primary and secondary somatosensory cortex

    SPG = sphenopalatine ganglion SuS = superior salivary nucleus

    TCC = trigeminocervical complex TG = trigeminal ganglion

    V1/V2 = primary and secondary visual cortex

    Presenter Presentation Notes Goadsby PJ, Holland PR, Martins-Oliveira M, Hoffmann J, Schankin C, Akerman S. Pathophysiology of Migraine: A Disorder of Sensory Processing. Physiol Rev. 2017;97(2):553-622.

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    MIGRAINE PATHOPHYSIOLOGY Genetic Basis for Migraine  Many genes implicated though none individually

    convincing for all “run-of-the-mill” migraine  Likely due to heterogeneity rather than lack of correlation May explain why subsets of patients seem to respond better to

    certain drug classes than others

     For example, familial hemiplegic migraine:  SCN1A (Nav1.1)

     Severe myoclonic epilepsy of infancy (SMEI = Dravet syndrome)  Generalized epilepsy with febrile seizures plus (GEFS+)

     CACNA1A (P/Q type Cav2.1)  ATP1A2 (Na+/K+-ATPase)

    Presenter Presentation Notes Goadsby PJ, Holland PR, Martins-Oliveira M, Hoffmann J, Schankin C, Akerman S. Pathophysiology of Migraine: A Disorder of Sensory Processing. Physiol Rev. 2017;97(2):553-622.

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    MIGRAINE PATHOPHYSIOLOGY Genetic Basis for Migraine

    from Sutherland and Griffiths

    Presenter Presentation Notes Sutherland HG, Griffiths LR. Genetics of Migraine: Insights into the Molecular Basis of Migraine Disorders. Headache. 2017 Apr;57(4):537-569. doi: 10.1111/head.13053.

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    MIGRAINE PATHOPHYSIOLOGY Common Triggers Conceptualize: Any sudden change can cause a CSD “chemical wave”  Hormonal changes

     Menarche  Menses  Pregnancy  Menopause

     Stress or stress let-down  Insomnia  Barometric pressure changes

     Weather fronts  Altitudinal changes

     Smells  Perfumes, colognes  Candles, fumes, smoke

     Bright lights

     Stimulants  Caffeine  Energy drinks  Nasal decongestants (i.e.,

    pseudoephedrine, phenylephrine)  Other sympathomimetics

     Foods  Monosodium glutamate (MSG)  Nitrates & nitrites (e.g., deli meats)  Tyramine (e.g., aged cheeses)  Artificial sweeteners  Alcohol  Others

     Skipping meals  Dehydration

    Presenter Presentation Notes Goadsby PJ, Holland PR, Martins-Oliveira M, Hoffmann J, Schankin C, Akerman S. Pathophysiology of Migraine: A Disorder of Sensory Processing. Physiol Rev. 2017;97(2):553-622. Gordon DL. Headache and Migraine. Oct. 24, 2018 PowerPoint presentation to medical students at the University of Oklahoma College of Medicine.

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    MIGRAINE PATHOPHYSIOLOGY How To Describe Migraine To Patients  Migraine does not mean “bad headache”! People can

    even have migraine attacks with no headaches!  Migraine tends to run in families and is something you

    were likely born with.  Having migraine means your body is more sensitive to

    the chemical changes that happen in your brain.  Many things can trigger “attacks.” For people with

    migraine, fewer triggers are required to start attacks.  Because your brain is a tangle of wires controlling the

    rest of your body, when the wires are overly sensitive during an attack many types of symptoms can occur…

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    NEUROTRANSMITTERS IN MIGRAINE

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    NEUROTRANSMITTERS IN MIGRAINE Overview  Serotonin (5-HT)  CGRP (calcitonin gene-

    related peptide)  Norepinephrine (NE)  Histamine

     Others  Substance P Nitric oxide (NO) Arachidonic acid

    metabolites Pituitary adenylate

    cyclase-activating polypeptide (PACAP)

    Vasoactive intestinal peptide (VIP)

    …and many more

    Presenter Presentation Notes Ayata C, Jin H, Kudo C, Dalkara T, Moskowitz MA. Suppression of Cortical Spreading Depression in Migraine Prophylaxis. Ann Neurol. 2006;59:65