Multi-mechanisms in Migraine

1. Multi-mechanisms in Migraine Recent Advances in Pathophysiology and Diagnosis Frank O’Donnell D.O.

2. Migraine Presentation: Contents • Impact of migraine & what patients want from treatment • Pathophysiology – Migraine is a multimechanistic disease • In-depth look at the multiple mechanisms of disease at a cellular level • Inflammation • Vasodilation & edema • Activation of pain receptors • Peripheral & central sensitization • Referred pain • Summary animation • Resulting insights into diagnostic accuracy

3. Impact of Migraine & What Patients Want from Treatment

4. Prevalence: The Impact of Migraine • Currently 28 million migraine sufferers age 12+ in the United States • 21 million females • 7 million males • Migraine prevalence peaks in the 25-55 age group • 25% of women age 18-49 suffer from migraine • 1 in 4 households has at least 1 migraine sufferer Lipton RB et al. Headache. 2001;41:638-657.

5. What Patients Want from Treatment • Top 5 patient treatment desires1 • Have relief from pain • Avoid recurrences • Quick symptom relief • Minimal side effects • Return to normal activities • Current therapies fall short on patient satisfaction for these desires 25-35% non-responders in clinical trials less then 2/3 of patients respond 3/3 attacks Lipton, et al. Headache. 1999;39(Suppl 2):S20-S26.

6. Triptan non-responders HA intense at baseline Severe nausea and vomiting Less autonomic signs Less menstrual influence Onset at early age High body mass index Increased anxiety

7. Why Patients Fail • Not able to treat early • Low and inconsistent oral absorption • Unrecognized analgesic overuse • Medical and psychiatric co-morbidities • 5HT receptor polymorphisms

8. Migraine Pathophysiology

9. Migraine Activity May Start in the Cortex

10. CSD Stimulates Trigeminal Sensory Fibers (TSF) Trigeminal nerve fibers in the meningeal blood vessel 1 2 3

11. 1 2 3 4 5 6 Release of CGRP, substance P & Inflammatory Cytokines

14. Arachidonic Cascade Results in Prostaglandins • Kinins facilitate the production of Cyclooxygenases • Cyclooxygenases convert arachidonic acid to prostaglandins 1 2 3

15. Vasodilation and Edema in Local Blood Vessels • CGRP and prostaglandins cause inflammation and vasodilation of cerebral and meningeal blood vessels as well as surrounding tissue

17. Activation of Nociceptors • The inflammation and edema activate peripheral meningeal pain receptors called nociceptors Nociceptors transmit signals to the trigeminal ganglion and the TNC

19. Review: Anatomy of the Trigeminal Nerve

20. TNC Transmits Pain Signals to Thalamus & Cerebral Cortex • Patient first experiences the sensation of pain

21. Multiple Mechanism Prior to Pain Perception

22. Consequences of Sustained Pain Transmission • Continuous stimulation of the trigeminal ganglion • Activation of the TNC • Activation of the surrounding glial cells

23. Glial Cells • Glial cells are now thought to have neuronal modulatory activity

24. Glial Cells Release Prostaglandin • Independent of signals from trigeminal ganglion

25. Prolonged TNC Stimulation May Lead to Central Sensitization • Cutaneous allodynia is a marker for central sensitization, which when present during a migraine, may make the migraine episode more difficult to treat • A sustained pain-free response is harder to achieve

27. Patients often avoid 1 or more of the following activities because of cutaneousallodynia • Combing hair • Pulling hair back (ponytail) • Shaving • Wearing eyeglasses • Wearing contact lenses • Wearing jewelry • Wearing snug clothing • Using a heavy blanket in bed • Allowing shower water to hit the face (“it feels like pins and needles”) • Resting the face on the pillow on the migraine side • Rubbing back of neck • Cooking (“the heat is too much”) • Breathing through the nose on cold days (“it burns”) Symptoms of Central Sensitization Burstein R et al. Ann Neurol. 2000;47:614-624. Burstein R et al. Brain. 2000;123:1703-1709.

28. TNC Activation Results in Referred Pain • Pain can be referred to any of three branches of the trigeminal and/or cervical nerves & thus pain can be perceived on one or both sides of the head, around the eyes or sinuses, and in the posterior area of the head and neck.

29. Cranial Parasympathetic Activation • Activated TNC can stimulate superior salivatory nucleus causing parasympathetic activation • Parasympathetic activation can cause sinus-like symptoms during a migraine attack

32. Multiple Mechanisms of Migraine • Cortical spreading depression • Vasodilation • Inflammation • Nociception • Peripheral sensitization • Central neuronal sensitization • Referred pain

33. Animation

34. Conclusions • There are 28 million migraine sufferers in the United States • Migraine is a multimechanistic disease • Vasodilation • Inflammation • Nociception • Peripheral sensitization • Central neuronal sensitization • Referred pain • Current therapies fall short on addressing all of these mechanisms • A thorough understanding of migraine pathophysiology may explain why many patients are misdiagnosed • As sinus headache: due to symptoms like sinus congestion, rhinorrhea and sinus pain • As tension headache: due to symptoms like non-throbbing bilateral, posterior head and/or neck pain