Understanding the Pathophysiology of Migraine Pain
| Status: | Recruiting |
|---|---|
| Conditions: | Migraine Headaches |
| Therapuetic Areas: | Neurology |
| Healthy: | No |
| Age Range: | 18 - 80 |
| Updated: | 4/26/2018 |
| Start Date: | January 2017 |
| End Date: | June 2019 |
| Contact: | Andrew J Kobets, MD |
| Email: | akobets@montefiore.org |
| Phone: | 7189207400 |
Understanding the Role of the External Carotid Artery in 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.
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.
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
We found this trial at
1
site
3550 Jerome Avenue
Bronx, New York 10467
Bronx, New York 10467
(718) 920-4321
Phone: 718-920-7400
Montefiore Medical Center As the academic medical center and University Hospital for Albert Einstein College...
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