Understanding the Pathophysiology of Migraine Pain

Migraine is the most common headache disorder, prevalent in 18% of females and 6% of males. Emergency room visits, physician consults, hospitalizations, medications, and indirect costs such as lost work days and decreased productivity place the global economic burden of migraines at over 20 billion dollars. It is prevalent in 28 million people in the US alone. Symptoms include unilateral, throbbing, debilitating headache pain accompanied by nausea, vomiting, photophobia, and phonophobia. Upwards of 75% of migraine patients have reduced functionability, have lost time at work, and 1/3 of patients require bed rest to manage the symptoms. The health-related impact on quality of life was comparable with that experienced by patients with congestive heart failure, hypertension, or diabetes. While the burden of migraines on our society is clear, the pathophysiology of migraines remains largely unknown. The trigeminovascular system, including the external and internal carotid arteries and their associated sensory fibers which subserve the head have long been implicated in the pain and cutaneous allodynia experienced by migraine patients. Wolff in 1953, was the first to posit that migraine headache pain is the caused by dilation or circumferential expansion of the extracranial carotid artery. He demonstrated that migraineurs had twice the pulse amplitude in their external carotid arteries compared to control subjects and these changes were directly correlated to migraine symptoms. In a 2008 study, randomized migraineurs received nitroglycerin via peripheral IV or placebo for 20 minutes prior to obtaining magnetic resonance angiography (MRA). Nitroglycerin, a potent dilator of blood vessels, reliably induced migraine-like pain in up to 80% of patients, and transient dilation of vessels of up to nearly 40%, mostly in the extracranial vessels. Sumatriptan's efficacy in migraine relief provides further evidence for this theory, as it is a selective extracranial vessel constrictor which does not cross the blood brain barrier. The goal of this current work is to utilize the direct, real-time angiography, which provides a high resolution map of vasculature, and demonstrate changes in vessel flow in patients who have migraine headache attacks. This information may guide therapeutic interventions in the future in order to better treat these migraine patients.

The goals of the current study will be to demonstrate time-linked headache pain after super-selectively administration of vasodilatory medications to external carotid artery branches, and then observe vessel changes and presumed headache relief with transient occlusion of the same vessel. This work will be the first study to attempt to correlate the onset of headache pain with selective vessel dilation as seen on angiography, which has spatial and temporal resolution far superior to MRA imaging. It will also test the effect of transient vessel occlusion in this setting for possible relief of symptoms. This novel approach to migraine evaluation could advance the understanding of the disorder and steer future research towards more effective management of migraine pain. Only patients who have failed all medical and non-invasive therapies will be considered for this study. Subjects will be evaluated by history and physical during a clinic visit for their migraines and the 'pre-angiography' screening will be performed at that time. A thorough history of their migraine symptomatology, if they agree to participate, will be obtained via questionnaire, including: severity, location, quality, alleviating and exacerbating symptoms, medications used, associated symptoms, frequency, and degree of debilitation. This information will be collected regarding their migraines uniquely for this study. The patients will also be given a headache log with each one of these measures as a column with space in each row to describe individual migraine episodes between their first clinic visit and their angiogram date. After this clinic visit, they will be scheduled for angiography between 2 and 4 weeks for the evaluation of their migraines. Their headache logs will be collected prior to their procedures. The main portion of this study will occur during a single angiography session and the following 5 hours post-procedure period during which the patient will be monitored closely as part of standard post-angiogram care. An anesthesiologist will be present throughout the procedure and available for medication review and administration as needed. The patients will sign a consent form at the start of the day and will be reminded that they have the option of not participating in the study and continuing their normal migraine treatment. If they do choose to participate, the patients will be brought to the angiography suite and transferred to the angiogram table. The patient will be prepped and draped in standard fashion for an angiogram and given instructions regarding the procedure for the day. The patient will receive local lidocaine at their groin site to minimize discomfort during standard arterial access for the purposes of the angiogram. Catheterization will commence into the external carotid artery. At this time, the patient's headache history will guide the decision for first vessel cannulation. If the patient has frontal migraines, the internal maxillary artery will be cannulated, for parietal headaches the focus will be on the superficial temporal artery, and the occipital artery for posterior, occipitally located symptoms, all on the side of the patient's migraines. A microcatheter will be placed at the origin of each respective artery and a control contrast injection will be performed to determine baseline vessel caliber and blood flow. Patients will be asked at this time if they are experiencing any pain or discomfort. If none, nitroglycerin will be drawn up and injected at a volume of 200µg diluted in 10ml saline into these vessels only. This is a standard injection dose for vasodilation for this medication and it is routinely available and used to treat vasospasm, or vasoconstriction that occurs after subarachnoid hemorrhage in the angiography suite. This dose has also been used in several cranial and cardiac studies and has not been association with adverse reactions related to systemic spread. The expectation is that this small dose will not reach systemic circulation. After 5 minutes, another contrast run will be performed to determine any change in vessel size and the patient will be questioned about any headache symptoms. After another 5 minutes, another contrast run will be performed to see if the nitroglycerin is still effective. If the patient describes no symptoms, the focus will be shifted to one of the other 2 external carotid artery branches to test them for the induction of headaches using the same nitroglycerin protocol. Each vessel will be evaluated for a full 10 minutes and if no vessel causes headache pain, the study will be terminated after a final control injection and femoral sheath removal. Pressure on the groin will be held for 20 minutes and the patient will be taken to the recovery room and monitored lying flat, as in standard fashion for 5 hours before being discharged home in order to prevent groin hematoma. They will again be evaluated for headaches or pain hourly until discharge, and be given another headache log to complete prior to their 2 week follow-up visit. The headache log will be collected at that time and this will complete the study for the patient. If any vessel immediately, or with time produces headache pain, the patient will be queried regarding the type and quality of the headache, and asked if it is similar to their migraines. A 10 minute angiogram will be repeated at the vessel evaluated. With persistent headaches, a microballoon will be brought to the vessel origin, and it will be inflated to block flow in this vessel for 5 minutes before being deflated. As stated previously, there is no risk to occlusion of these vessels permanently, and certainly not temporarily as will be performed as part of this protocol. These non-critical vessels have dense anastomotic networks and are safe to occlude. Symptoms will be evaluated to see if any subside as a result of their occlusion. Five minutes after the balloon is deflated, another contrast run will be performed to evaluate the caliber of the studied vessel. After this run, the groin sheath will be removed and the above protocol will be followed until outpatient follow-up. If headache symptoms do not subside, the patient will be administered standard pain medication, fentanyl, which is given routinely during angiography at a dose of 25mcg to abate their pain. This is a low, tolerable, and safe dose that will be given with the assistance of our anesthesia colleagues, if necessary. Their headache pain will be closely monitored during the 5 hour recovery period, and given 1 more 25mcg dose during this period in order to fully subside any pain the patient still may have. This angiogram will take approximately 30 minutes to complete, and it is a low risk procedure.. The vessels studied diagnostically will be solely extracranial and completely separate from intracranial vessels. Any anomalous communication identified between extracranial and intracranial vessels will automatically disqualify a patient from participation in this study. Despite some minor discomfort from the groin puncture for the patient, with the assistance of an anesthesiologist the pain intra- and post-procedurally experienced by patients will be well controlled. The patient may also opt to receive the rescue pain medication at any time during the angiogram and discontinue the study. As stated previously, the extracranial vascular circulation has a large anastomotic network such that a single vessel sacrifice can be performed without great risk. These vessels are sacrificed without sequelae intraoperatively routinely when performing craniotomies. In cases where a provocative artery can be found, occlusion of that vessel can lead to improved symptoms, as tested by temporary balloon occlusion without great risk. It is the hope that this pilot work to guide future interventions to control blood flow in these offending vessels, to see if migraines abate permanently with vessel removal from circulation. If these hypotheses are correct, interventions may be created to minimize patient's need for medication, improve their quality of life, and free them from the debilitation of their migraines.

Subjects who will be administered 200 micrograms of nitroglycerin once into branches of their external carotid artery to determine the role of dilation of this artery to cause migraine-like pain

Relief of induced migraine pain with temporary balloon occlusion of the dilated artery. Standard pain medication will also be available for treatment

Monitoring for retroperitoneal hematoma, vascular injury, infection, contrast reaction, worsening contralateral headache symptoms, new neurologic deficit peri-procedurally until discharge

Inclusion Criteria: Subjects with a documented diagnosis of migraine by a neurologist Subjects refractory to standard migraine therapy with persistent severe, debilitating symptoms Subjects without changes to their neurological exam within the preceding 6 months Migraines at least twice a month Migraines unique and distinguishable from other non-migraine headache pain Subjects must sign a consent form for both angiography and for participation in this study, and must be willing to undergo angiography for the evaluation of their symptoms Exclusion Criteria: Subjects taking vasoactive drugs including epinephrine, norepinephrine, dopamine, dobutamine, isoprenaline, dopexamine, milrinone, amrinon, levosimendan, glucagon, phenylephrine, metaraminol, ephedrine, vasopressin, digoxin, and levothyroxine Subjects with underlying cardiac pathology including but not limited to coronary artery disease, heart attacks, or severe atherosclerosis, Subjects with severe pulmonary disease requiring supplemental oxygen therapy Subjects taking medications similar to nitroglycerin such as phosphodiesterase inhibitors Subjects with contraindications to nitroglycerin or calcium channel blocker use Subjects who have had coffee, tea, or alcohol in the 12 hours before the start of the angiogram Subjects having other headache conditions or pain syndromes Subjects with prior intracranial therapies or craniotomies for management of any intracranial lesions Subjects in whom the angiography demonstrates severe vessel tortuosity or stenosis, vasospasm not responsive to medical therapy, or abnormal communication between intracranial and extracranial vessels either in the past or during the study procedure Subjects who are not able to reliably report symptoms Subjects who do not consent to participate Subjects who are pregnant and children

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