Understanding the Pathophysiology of Migraine Pain
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.
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