Migraine DisordersNCT03026101
Understanding the Pathophysiology of Migraine Pain
A study testing Nitroglycerin in people with Migraine Disorders and Migraine, Classic, run by Montefiore Medical Center at 1 site in United States.
Trial summary
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. Read more about this study
- Who is it for?
- Ages 18 to 80 years
- Conditions the study is for
- Migraine Disorders, Migraine, Classic, Migraine Without Aura
- What is being tested?
- Nitroglycerin
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 4 participants
- Where
- 1 siteUnited States
- Study dates
- Jan 2017to 24 Apr 2025
- Phase
- Interventional
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 80 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- No changes to neurological exam within the preceding 6 months
- Requirement of a diagnostic cerebral angiogram for a previously treated aneurysm or arteriovenous malformation with no history of persistent disease
- A documented diagnosis of migraine made by a neurologist
- Migraines that are refractory to standard migraine pharmacologic treatment, with or without aura, either prophylactic or abortive, with persistent severe, debilitating symptoms
- Experience migraine symptoms at least twice a month
- Migraines symptomology which is discernible 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
Who cannot join
- Patients with persistent intracranial vascular anomalies, such as aneurysms, which remain untreated, in whole or in part
- Patients taking vasoactive drugs including epinephrine, norepinephrine, dopamine, dobutamine, isoprenaline, dopexamine, milrinone, amrinon, levosimendan, glucagon, phenylephrine, metaraminol, ephedrine, vasopressin, digoxin, and levothyroxine
- Patients with underlying cardiac pathology including but not limited to coronary artery disease, heart attacks, or severe atherosclerosis
- Patients taking medications such as phosphodiesterase 5 (PDE5) inhibitors or other nitroglycerin analogues
- Patients with pulmonary disease requiring supplemental oxygen therapy
- Patients with contraindications to nitroglycerin or calcium channel blocker use
Show all 17Show fewer
- Patients who have had coffee, tea, or alcohol in the 12 hours before the start of the angiogram
- Patients having other headache conditions, pain syndromes, or prior intracranial therapies or craniotomies for management of any vascular lesions that would require angiography for surveillance and confound their evaluation of their migraine pain
- Patients in whom the angiography demonstrates the anatomy is not appropriate for endovascular treatment, due to conditions such as:
- Severe vessel tortuosity or stenosis
- Vasospasm not responsive to medical therapy
- Abnormal communication between intracranial and extracranial vessels either in the past or during the study procedure
- Patients who are not able to reliably report symptoms
- Patients without the capacity to consent
- Patients who do not consent to participate
- Patients who are pregnant
- Children
Trial locations and contacts
1 site in 1 country.
United States1 site
Montefiore Medical Center
The Bronx, New York, 10467
About this study
Official title: 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.
Read the detailed description
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.
- Conditions
- Migraine Disorders, Migraine, Classic, Migraine Without Aura
- Being tested
- Nitroglycerin
- Medical subject headings
- Migraine Disorders, Migraine with Aura, Migraine without Aura
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
NitroglycerinOther
Also called Nitrostat
Intra-arterial adminstration to dilate external carotid artery branches to replicate migraine pain
| Study group | Role | What they receive |
|---|---|---|
| Migraine Intervention | Experimental | A catheter will be placed in the symptomatic side external carotid artery and a diagnostic angiogram will be performed. The diameter of the occipital artery, superficial temporal artery and middle meningeal artery will be measured. Depending on the location of the headache superselective catheterization with microcatheter will be placed in either superficial temporal artery, occipital artery or middle meningeal artery. A volume of 50µg of nitroglycerin diluted in 10ml saline will be injected into the branch of interest dependent on laterality and location of symptoms over 30 seconds, to be delivered into these vessels only. 1 minute after superselective nitroglycerin injection the patient will be questioned as to whether the headache has been induced. A follow up diagnostic angiogram of the external carotid artery will be performed 3 minutes after injection. If there is no response to the lower 50µg, a dose of 150µg nitroglycerin in 10ml saline will be administered. Receives: Other: Nitroglycerin |
What is being measured
The primary outcome is the main question the study is designed to answer.
Migraine
The reporting of migraine-like pain after nitroglycerin administration
Measured: 10 minutes
Secondary outcomes (19)
Migraine log pre-procedure: severity measure
Severity of migraines for 2 weeks prior to angiogram
Measured: 2 weeks
Migraine log pre-procedure: frequency measure
Frequency of migraines for 2 weeks prior to angiogram
Measured: 2 weeks
Migraine log pre-procedure: quality measure
Quality of migraines for 2 weeks prior to angiogram
Measured: 2 weeks
Migraine log pre-procedure: location measure
Location of migraines for 2 weeks prior to angiogram
Measured: 2 weeks
Migraine log pre-procedure: alleviating factor measure
Alleviating factors of migraines for 2 weeks prior to angiogram
Measured: 2 weeks
Migraine log pre-procedure: aggravating factor measure
Aggravating factors of migraines for 2 weeks prior to angiogram
Measured: 2 weeks
Migraine log pre-procedure: associated symptom measure
Associated symptoms of migraines for 2 weeks prior to angiogram
Measured: 2 weeks
Migraine log pre-procedure: therapies utilized measure
Therapies utilized for migraines for 2 weeks prior to angiogram
Measured: 2 weeks
Artery dilation
Enlargement of the diameter of the vessel of interest after nitroglycerin administration
Measured: 10 minutes
Migraine pain relief
Relief of induced migraine pain with temporary balloon occlusion of the dilated artery. Standard pain medication will also be available for treatment
Measured: 20 minutes
Adverse reactions
Monitoring for retroperitoneal hematoma, vascular injury, infection, contrast reaction, worsening contralateral headache symptoms, new neurologic deficit peri-procedurally until discharge
Measured: 6 hours
Migraine log follow-up post-procedure: severity measure
Severity of migraines for 2 weeks post-angiogram
Measured: 2 weeks
Migraine log follow-up post-procedure: frequency measure
Frequency of migraines for 2 weeks post-angiogram
Measured: 2 weeks
Migraine log follow-up post-procedure: quality measure
Quality of migraines for 2 weeks post-angiogram
Measured: 2 weeks
Migraine log follow-up post-procedure: location measure
Location of migraines for 2 weeks post-angiogram
Measured: 2 weeks
Migraine log follow-up post-procedure: alleviating factors measure
Alleviating factors of migraines for 2 weeks post-angiogram
Measured: 2 weeks
Migraine log follow-up post-procedure: aggravating factor measure
Aggravating factors of migraines for 2 weeks post-angiogram
Measured: 2 weeks
Migraine log follow-up post-procedure: associated factor measure
Associated symptoms of migraines for 2 weeks post-angiogram
Measured: 2 weeks
Migraine log follow-up post-procedure: therapies utilized measure
Therapies utilized for 2 weeks after angiogram until follow-up clinic visit
Measured: 2 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted20 Jan 2017 (estimated)
- Study startJan 2017
- Primary completion24 Apr 2025
- Study completion24 Apr 2025
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (38)Papers the sponsor has linked to this study.
- Other trials for Migraine DisordersStudies of the same condition, open and under way.
- More trials run by Montefiore Medical CenterThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Diagnosis
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 4 participants (actual)
Sponsor and investigators
- Lead sponsor
- Montefiore Medical Center
- Sponsor type
- University, hospital or other
- Collaborators
- Johns Hopkins University
- Responsible party
- Sponsor
- Investigators
- David J Altschul, MD, Principal investigator, Montefiore Medical Center
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03026101
- Sponsor's protocol ID
- 2017-8335
- Status last verified
- Aug 2025
- First submitted
- 27 Dec 2016
- Last updated
- 20 Aug 2025
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Schoenen J. Hypoxia, a turning point in migraine pathogenesis? Brain. 2016 Mar;139(Pt 3):644-7. doi: 10.1093/brain/awv402. No abstract available.
PubMed 26917583Stoeckelhuber BM, Suttmann I, Stoeckelhuber M, Kueffer G. Comparison of the vasodilating effect of nitroglycerin, verapamil, and tolazoline in hand angiography. J Vasc Interv Radiol. 2003 Jun;14(6):749-54. doi: 10.1097/01.rvi.0000079984.80153.5e.
PubMed 12817042Maruhashi T, Soga J, Fujimura N, Idei N, Mikami S, Iwamoto Y, Kajikawa M, Matsumoto T, Hidaka T, Kihara Y, Chayama K, Noma K, Nakashima A, Goto C, Higashi Y. Nitroglycerine-induced vasodilation for assessment of vascular function: a comparison with flow-mediated vasodilation. Arterioscler Thromb Vasc Biol. 2013 Jun;33(6):1401-8. doi: 10.1161/ATVBAHA.112.300934. Epub 2013 Mar 21.
PubMed 23520168McNiff EF, Yacobi A, Young-Chang FM, Golden LH, Goldfarb A, Fung HL. Nitroglycerin pharmacokinetics after intravenous infusion in normal subjects. J Pharm Sci. 1981 Sep;70(9):1054-8. doi: 10.1002/jps.2600700923.
PubMed 6101155Ferrari MD. The economic burden of migraine to society. Pharmacoeconomics. 1998 Jun;13(6):667-76. doi: 10.2165/00019053-199813060-00003.
PubMed 10179702Lipton RB, Bigal ME, Diamond M, Freitag F, Reed ML, Stewart WF; AMPP Advisory Group. Migraine prevalence, disease burden, and the need for preventive therapy. Neurology. 2007 Jan 30;68(5):343-9. doi: 10.1212/01.wnl.0000252808.97649.21.
PubMed 17261680Goadsby PJ, Charbit AR, Andreou AP, Akerman S, Holland PR. Neurobiology of migraine. Neuroscience. 2009 Jun 30;161(2):327-41. doi: 10.1016/j.neuroscience.2009.03.019. Epub 2009 Mar 19.
PubMed 19303917Costa C, Tozzi A, Rainero I, Cupini LM, Calabresi P, Ayata C, Sarchielli P. Cortical spreading depression as a target for anti-migraine agents. J Headache Pain. 2013 Jul 23;14(1):62. doi: 10.1186/1129-2377-14-62.
PubMed 23879550Evans RW. Diagnostic testing for migraine and other primary headaches. Neurol Clin. 2009 May;27(2):393-415. doi: 10.1016/j.ncl.2008.11.009.
PubMed 19289222Schoonman GG, van der Grond J, Kortmann C, van der Geest RJ, Terwindt GM, Ferrari MD. Migraine headache is not associated with cerebral or meningeal vasodilatation--a 3T magnetic resonance angiography study. Brain. 2008 Aug;131(Pt 8):2192-200. doi: 10.1093/brain/awn094. Epub 2008 May 23.
PubMed 18502781Nagata E, Moriguchi H, Takizawa S, Horie T, Yanagimachi N, Takagi S. The middle meningial artery during a migraine attack: 3T magnetic resonance angiography study. Intern Med. 2009;48(24):2133-5. doi: 10.2169/internalmedicine.48.2565.
PubMed 20009407Asghar MS, Hansen AE, Kapijimpanga T, van der Geest RJ, van der Koning P, Larsson HB, Olesen J, Ashina M. Dilation by CGRP of middle meningeal artery and reversal by sumatriptan in normal volunteers. Neurology. 2010 Oct 26;75(17):1520-6. doi: 10.1212/WNL.0b013e3181f9626a.
PubMed 20975053Amin FM, Asghar MS, Hougaard A, Hansen AE, Larsen VA, de Koning PJ, Larsson HB, Olesen J, Ashina M. Magnetic resonance angiography of intracranial and extracranial arteries in patients with spontaneous migraine without aura: a cross-sectional study. Lancet Neurol. 2013 May;12(5):454-61. doi: 10.1016/S1474-4422(13)70067-X. Epub 2013 Apr 9.
PubMed 23578775Arngrim N, Schytz HW, Britze J, Amin FM, Vestergaard MB, Hougaard A, Wolfram F, de Koning PJ, Olsen KS, Secher NH, Larsson HB, Olesen J, Ashina M. Migraine induced by hypoxia: an MRI spectroscopy and angiography study. Brain. 2016 Mar;139(Pt 3):723-37. doi: 10.1093/brain/awv359. Epub 2015 Dec 16.
PubMed 26674653Olesen J. The role of nitric oxide (NO) in migraine, tension-type headache and cluster headache. Pharmacol Ther. 2008 Nov;120(2):157-71. doi: 10.1016/j.pharmthera.2008.08.003. Epub 2008 Aug 23.
PubMed 18789357
Study at a glance
From the registry record, last updated by the sponsor on 20 Aug 2025. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Understanding the Role of the External Carotid Artery in the Pathophysiology of Migraine Pain
- ClinicalTrials.gov ID
- NCT03026101
- Acronym / sponsor ID
- 2017-8335
- Conditions
- Migraine Disorders, Migraine, Classic, Migraine Without Aura
- Study type
- Interventional
- Recruitment status
- Terminated
- Enrolment
- 4 participants (actual)
- Lead sponsor
- Montefiore Medical CenterUniversity, hospital or other
- Collaborators
- Johns Hopkins University
- Study start
- Jan 2017 (actual)
- Primary completion
- 24 Apr 2025 (actual)
- Study completion
- 24 Apr 2025 (actual)
- First posted
- 20 Jan 2017 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Detailed description
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.
Study design
- Primary purpose
- Diagnosis
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Migraine Intervention | Experimental | Other: NitroglycerinA catheter will be placed in the symptomatic side external carotid artery and a diagnostic angiogram will be performed. The diameter of the occipital artery, superficial temporal artery and middle meningeal artery will be measured. Depending on the location of the headache superselective catheterization with microcatheter will be placed in either superficial temporal artery, occipital artery or middle meningeal artery. A volume of 50µg of nitroglycerin diluted in 10ml saline will be injected into the branch of interest dependent on laterality and location of symptoms over 30 seconds, to be delivered into these vessels only. 1 minute after superselective nitroglycerin injection the patient will be questioned as to whether the headache has been induced. A follow up diagnostic angiogram of the external carotid artery will be performed 3 minutes after injection. If there is no response to the lower 50µg, a dose of 150µg nitroglycerin in 10ml saline will be administered. |
Who may qualify
- Ages
- 18 to 80 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (7 listed)
- No changes to neurological exam within the preceding 6 months
- Requirement of a diagnostic cerebral angiogram for a previously treated aneurysm or arteriovenous malformation with no history of persistent disease
- A documented diagnosis of migraine made by a neurologist
- Migraines that are refractory to standard migraine pharmacologic treatment, with or without aura, either prophylactic or abortive, with persistent severe, debilitating symptoms
- Experience migraine symptoms at least twice a month
Key exclusion criteria (17 listed)
- Patients with persistent intracranial vascular anomalies, such as aneurysms, which remain untreated, in whole or in part
- Patients taking vasoactive drugs including epinephrine, norepinephrine, dopamine, dobutamine, isoprenaline, dopexamine, milrinone, amrinon, levosimendan, glucagon, phenylephrine, metaraminol, ephedrine, vasopressin, digoxin, and levothyroxine
- Patients with underlying cardiac pathology including but not limited to coronary artery disease, heart attacks, or severe atherosclerosis
- Patients taking medications such as phosphodiesterase 5 (PDE5) inhibitors or other nitroglycerin analogues
- Patients with pulmonary disease requiring supplemental oxygen therapy
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| NitroglycerinAlso: NitrostatIntra-arterial adminstration to dilate external carotid artery branches to replicate migraine pain | Other | Migraine Intervention |
Primary outcome
Migraine
Time frame: 10 minutes
The reporting of migraine-like pain after nitroglycerin administration
19 secondary outcomes
Migraine log pre-procedure: severity measure
Time frame: 2 weeks
Migraine log pre-procedure: frequency measure
Time frame: 2 weeks
Migraine log pre-procedure: quality measure
Time frame: 2 weeks
Migraine log pre-procedure: location measure
Time frame: 2 weeks
Migraine log pre-procedure: alleviating factor measure
Time frame: 2 weeks
Migraine log pre-procedure: aggravating factor measure
Time frame: 2 weeks
Migraine log pre-procedure: associated symptom measure
Time frame: 2 weeks
Migraine log pre-procedure: therapies utilized measure
Time frame: 2 weeks
Artery dilation
Time frame: 10 minutes
Migraine pain relief
Time frame: 20 minutes
Adverse reactions
Time frame: 6 hours
Migraine log follow-up post-procedure: severity measure
Time frame: 2 weeks
Migraine log follow-up post-procedure: frequency measure
Time frame: 2 weeks
Migraine log follow-up post-procedure: quality measure
Time frame: 2 weeks
Migraine log follow-up post-procedure: location measure
Time frame: 2 weeks
Migraine log follow-up post-procedure: alleviating factors measure
Time frame: 2 weeks
Migraine log follow-up post-procedure: aggravating factor measure
Time frame: 2 weeks
Migraine log follow-up post-procedure: associated factor measure
Time frame: 2 weeks
Migraine log follow-up post-procedure: therapies utilized measure
Time frame: 2 weeks
Results and safety
The study was stopped early. Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 20 Aug 2025.
- Background: PubMed 26917583Schoenen J. Hypoxia, a turning point in migraine pathogenesis? Brain. 2016 Mar;139(Pt 3):644-7. doi: 10.1093/brain/awv402. No abstract available.
- Background: PubMed 12817042Stoeckelhuber BM, Suttmann I, Stoeckelhuber M, Kueffer G. Comparison of the vasodilating effect of nitroglycerin, verapamil, and tolazoline in hand angiography. J Vasc Interv Radiol. 2003 Jun;14(6):749-54. doi: 10.1097/01.rvi.0000079984.80153.5e.
- Background: PubMed 23520168Maruhashi T, Soga J, Fujimura N, Idei N, Mikami S, Iwamoto Y, Kajikawa M, Matsumoto T, Hidaka T, Kihara Y, Chayama K, Noma K, Nakashima A, Goto C, Higashi Y. Nitroglycerine-induced vasodilation for assessment of vascular function: a comparison with flow-mediated vasodilation. Arterioscler Thromb Vasc Biol. 2013 Jun;33(6):1401-8. doi: 10.1161/ATVBAHA.112.300934. Epub 2013 Mar 21.
- Background: PubMed 6101155McNiff EF, Yacobi A, Young-Chang FM, Golden LH, Goldfarb A, Fung HL. Nitroglycerin pharmacokinetics after intravenous infusion in normal subjects. J Pharm Sci. 1981 Sep;70(9):1054-8. doi: 10.1002/jps.2600700923.
- Background: PubMed 10179702Ferrari MD. The economic burden of migraine to society. Pharmacoeconomics. 1998 Jun;13(6):667-76. doi: 10.2165/00019053-199813060-00003.
- Background: PubMed 17261680Lipton RB, Bigal ME, Diamond M, Freitag F, Reed ML, Stewart WF; AMPP Advisory Group. Migraine prevalence, disease burden, and the need for preventive therapy. Neurology. 2007 Jan 30;68(5):343-9. doi: 10.1212/01.wnl.0000252808.97649.21.
- Background: PubMed 19303917Goadsby PJ, Charbit AR, Andreou AP, Akerman S, Holland PR. Neurobiology of migraine. Neuroscience. 2009 Jun 30;161(2):327-41. doi: 10.1016/j.neuroscience.2009.03.019. Epub 2009 Mar 19.
- Background: PubMed 23879550Costa C, Tozzi A, Rainero I, Cupini LM, Calabresi P, Ayata C, Sarchielli P. Cortical spreading depression as a target for anti-migraine agents. J Headache Pain. 2013 Jul 23;14(1):62. doi: 10.1186/1129-2377-14-62.
- Background: PubMed 19289222Evans RW. Diagnostic testing for migraine and other primary headaches. Neurol Clin. 2009 May;27(2):393-415. doi: 10.1016/j.ncl.2008.11.009.
- Background: PubMed 18502781Schoonman GG, van der Grond J, Kortmann C, van der Geest RJ, Terwindt GM, Ferrari MD. Migraine headache is not associated with cerebral or meningeal vasodilatation--a 3T magnetic resonance angiography study. Brain. 2008 Aug;131(Pt 8):2192-200. doi: 10.1093/brain/awn094. Epub 2008 May 23.
- Background: PubMed 20009407Nagata E, Moriguchi H, Takizawa S, Horie T, Yanagimachi N, Takagi S. The middle meningial artery during a migraine attack: 3T magnetic resonance angiography study. Intern Med. 2009;48(24):2133-5. doi: 10.2169/internalmedicine.48.2565.
- Background: PubMed 20975053Asghar MS, Hansen AE, Kapijimpanga T, van der Geest RJ, van der Koning P, Larsson HB, Olesen J, Ashina M. Dilation by CGRP of middle meningeal artery and reversal by sumatriptan in normal volunteers. Neurology. 2010 Oct 26;75(17):1520-6. doi: 10.1212/WNL.0b013e3181f9626a.
- Individual participant dataSharing planned: No
Related trials for Migraine Disorders
RecruitingObservational study
Study of the Glymphatic System in Migraine
Migraine
Active, not recruiting
Clinical and Neurophysiological Effects of tDCS to Visual and Motor Cortex in Migraine
Migraine
Active, not recruiting
App-Based Migraine Treatment: The Health enSuite Study
Migraine, Migraine With Aura
Enrolling by invitation
App-based Breathing Program for Migraine Relief
Migraine, Heart Rate Variability (HRV)
Recruiting
Marine Lipids Ease Painful TMD
Temporomandibular Disorder (TMD)
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
David J Altschul, MD principal investigator
Montefiore Medical Center
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing Nitroglycerin in people with Migraine Disorders and Migraine, Classic, run by Montefiore Medical Center at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 7 inclusion and 17 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: stopped early, as of the sponsor's last update on 20 Aug 2025. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
The study was stopped early. Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Migraine (time frame: 10 minutes). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03026101, which also lists 38 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 20 Aug 2025; AzTrials last refreshed its copy on 7 Nov 2026.