Clinical trial NCT03666663
Conditions: Migraine
Sponsor: University of California, San Francisco
Start date: 2019-02-01; Completion date: 2021-07-08
Enrollment: 10 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
RCT of Sphenopalatine Ganglion (SPG) Blocks using anesthetics vs. placebo for migraine.

Detailed description:
Chronic Migraine is a brain disorder with high prevalence. It is the 7th leading cause of disability worldwide according the WHO.

SPG block is a treatment for migraine that has been used for two decades. It can be done by needle injection of anesthetic to the region of the SPG. However, there are now multiple catheter devices that can be used to non-invasively administer anesthetic topically through the nasal cavity to the region of the SPG where the anesthetic is then absorbed through thin membranes covering the SPG.

Various anesthetic agents have been studied however currently, to our knowledge, there is no head to head comparison of the various anesthetics used. Studies of SPG blocks in the setting of chronic migraine are few as compared to the use of SPG as acute treatment for migraine.

With the use of an RCT, we aim to determine the overall efficacy of SPG blocks used at longer intervals than have been studied in the past as compared to placebo, as well as to examine the relative efficacy of the anesthetics used most commonly and studied for SPG blocks.

We will be using an FDA cleared device, the Sphenocath which was developed and registered with the FDA for this specific population and purpose. The study intervention is the standard practice in the UCSF Headache Center to perform SPG blocks for our patients with chronic migraine. The frequency we use in clinical practice and that we plan to study is less often than in previous studies of this intervention in this population.

Arms: arm 1: Participants will receive SPG blocks with lidocaine. arm 2: Participants will receive SPG blocks with bupivacaine arm 3: Participants will receive SPG blocks with ropivacaine arm 4: Participants will receive SPG blocks with placebo (saline)
Interventions: intervention 1: Lidocaine intervention 2: Bupivacaine intervention 3: Ropivacaine intervention 4: Placebo
Intervention descriptions: intervention 1: Nasal application using the Sphenocath device- cleared by FDA intervention 2: Nasal application using the Sphenocath device- cleared by FDA intervention 3: Nasal application using the Sphenocath device- cleared by FDA intervention 4: Placebo Saline using the Sphenocath device- cleared by FDA

Protocol documents:
Prot_SAP_000.pdf: 
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UCSF Headache Center 
Protocol
Sphenopalatine Ganglion (SPG) Block Randomized Placebo Controlled Study
11/29/2018
Version 1.6
Nina Riggins, MD
Department of Neurology
UCSF Headache Center
2330 Post Street, Suite 610
San Francisco, CA 94115
415-353-8393
Nina.Riggins@ucsf.edu
CONFIDENTIAL
NCT03666663


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Table of Contents:
1) Introduction
a) Project summary
i) Name and dosages of drugs
ii) Pharmaceutical class of drugs
iii) Structural formula of drugs
iv) Route of administration
2) Research Plan and Procedures
a) Hypothesis
b) Aims
c) Study Design
d) Background and significance
e) Preliminary studies
f) References
3) Procedure
a) Study drugs
b) Inclusion and exclusion criteria
c) Recruitment and Consent
d) Risks and Benefits 
e) Data collection
f) Safety monitoring


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1. Introduction
a. Project summary :
Chronic Migraine is a brain disorder with high prevalence. It is the 7th leading 
cause of disability worldwide according the WHO.
SPG block is a treatment for migraine that has been used for two decades. It can 
be done by needle injection of anesthetic to the region of the SPG. However, 
there are now multiple catheter devices that can be used to non-invasively 
administer anesthetic topically through the nasal cavity to the region of the SPG 
where the anesthetic is then absorbed through thin membranes covering the 
SPG.
Various anesthetic agents have been studied however currently, to our 
knowledge, there is no head to head comparison of the long versus short acting 
anesthetics. Studies of SPG blocks in the setting of chronic migraine are few as 
compared to the use of SPG as acute treatment for migraine.
With the use of an RCT, we aim to determine the overall efficacy of SPG blocks 
used at longer intervals than have been studied in the past as compared to 
placebo, as well as to examine the relative efficacy of the anesthetics used most 
commonly and studied for SPG blocks.
We will be using an FDA cleared device, the Sphenocath which was developed 
and registered with the FDA for this specific population and purpose. The study 
intervention is the standard practice in the UCSF Headache Center to perform 
SPG blocks for our patients with chronic migraine. The frequency we plan is less 
often than in previous studies of this intervention in this population. Patients will 
continue their usual headache care and treatments during the study.
i. Name and dosage of drugs 
a. 2% lidocaine, 0.5cc each nostril
b. 0.25% bupivacaine, 0.5cc each nostril
c. 0.5% ropivacaine, 0.5cc each nostril
d. Placebo (normal saline), 0.5cc each nostril
ii. Pharmaceutical class of drugs
Anesthetics 


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iii. Structural formula of active drugs
a. lidocaine : C14H22N2O
b. bupivacaine : C18H28N2O
c. ropivacaine : C17H26N2O
iv. Route of administration
1. Nasal application, via Sphenocath. This device is a small, flexible 
catheter which is a needle-less, topical applicator. It is FDA 
cleared for use to deliver anesthetic solution to the region of the 
SPG.  
2. Research Plan and Procedures
a. Hypothesis
Use of SPG (sphenopalatine-ganglion) blocks approximately every 2-4 
months for three treatments will be proven superior in migraine 
headache treatment as compared to placebo.
Using a placebo group and randomized control study design will control 
for the natural waxing and waning variation that can be expected to 
occur in migraine over the study duration.
Headache frequency and severity, as measured by daily standard 
headache diary, will improve with the use of repeated SPG Blocks every 
2-4 months by the end of the study period.
One of the anesthetics will be found to be more efficacious than the 
other.
There will be an improvement in the effect and duration of the therapeutic 
benefit of the each of the repeated SPG blocks with anesthetics over time.
Patients receiving active treatment will require fewer acute treatments 
and emergency room visits than those receiving placebo.
b. Aims 
i. To determine whether the use of SPG (sphenopalatine-ganglion) blocks 
less frequently than previously studied will still be effective in migraine 
headache prevention.
ii. To determine if there is a difference in efficacy between lidocaine and 
bupivacaine and ropivacaine
iii. To determine whether the repeated use of SPG blocks every 2-4 months 
for 3 treatments will have a cumulative effect with subsequent 


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treatments providing better and longer lasting effects on headache 
frequency and severity. 
iv. To determine if repetitive SPG blocks can reduce the need and use of 
acute treatments and emergency room visits
c.
Study Design
This will be a randomized, double blind, placebo controlled study of non-
invasive SPG blocks in patients with chronic migraine using the 
Sphenocath device.
Approximately 120 patients will be randomized in a 1:1:1:1 ratio to 
receive SPG block using lidocaine, or bupivacaine or ropivacaine or 
normal saline every 2 to 4 months for three treatments. There will be 
approximately 30 subjects in each group.
The study period will run approximately 8 months. 
During the study period participants will continue to use their usual 
headache medicines and treatments. Participation in this study will not 
change their other headache treatments.
d. Background and significance
The sphenopalatine ganglion is located in the pterygopalatine ganglia 
close to the sphenopalatine foramen and is located below the maxillary 
nerve as it crosses the fossa. The sphenopalatine ganglion has multiple 
connections to facial, trigeminal, parasympathetic and sympathetic 
systems which make it a promising target for migraine treatment.   (1,2,3)
SPG blocks are widely used as an acute treatment of migraine(4-7,) ; and 
other headache disorders (8-10) although the preventive effects (11) have 
not been widely studied .
SPG blocks are quite commonly performed at the headache center to 
treat chronic migraine, and patients report significant relief. We would 
like to determine if the frequency and medications that we use as our 
standard of care prove to be significantly better than placebo and also to 
see if there is a difference in the anesthetics that we usually instill.  


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e. Preliminary studies
The use of SPG blocks for head pain goes back over a century. Sluder in 
1908 was the first to describe injection of the sphenopalatine ganglion via 
the nasal approach and subsequently reported success with its use in 
headache, facial neuralgia, earache, and “lower-half headache”. (12)
Intranasal (IN) instillation of lidocaine has been studied as an acute 
treatment for migraine both in the emergency department and in the 
home setting. (13-16).
Maizels and Geiger (1999) in their placebo controlled study trained 
patients to self-administer the study solution intranasally (either 4% 
lidocaine vs placebo) (13). Fifty one subjects were instructed to treat 
every headache for 1 month. There were 95 headaches treated with IN 
lido and 108 headaches with placebo. Headache relief at 15 minutes was 
found to be markedly superior to placebo. 
Benefit of SPG blocks with various anesthetics has been shown to be 
helpful in other head pain syndromes including reducing pain atypical 
face pain and cluster headache. (8-10)
In migraine specifically, SPG blocks have been studied in various 
populations including acute migraine, chronic migraine, chronic migraine 
with medication overuse, and status migrainosus. (4-7,11)
There are various methods for performing SPG blocks some of which are 
more invasive and risk prone that using catheter application.
Suprazygomatic injections to the region of the SPG was studied as an 
acute migraine treatment by Mehta et al (2018) in a cohort study (4). 
They injected a mixture of steroid (dexamethasone) and 0.5% ropivacaine 
through the skin above the zygomatic arch, to the region of the SPG. 
Eighty eight patients received a total of 252 injections to block the 
SPG.  They reported no significant complications of the procedure. At 30 
minutes following treatment, the overall reduction of pain among 
patients was statistically significant.
Cady et al (2015) investigated a less invasive, novel device (Tx360), to 
perform SPG blocks for chronic migraine. (7) They performed a double-
blind, parallel-arm, placebo-controlled, randomized trial of 38 
patients.  They measured pain scores at baseline, 15 minutes, 30 minutes, 
and 24 hours post treatment. The active phase consisted of a series of 12 
SPG blocks with 0.5% bupivacaine or saline which were provided 2 times 


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per week for 6 weeks. All side effects were mild to moderate, short in 
duration, and resolved spontaneously. No subject withdrew because of 
side effects which included mouth numbness (18%), lacrimation (29%), 
and bad taste (15%). Patients treated with bupivacaine showed a 
significant reduction in their pain scores from baseline at all intervals. 
Headache Impact Test-6 (HIT-6) scores were statistically significantly 
decreased in subjects receiving treatments with bupivacaine from before 
treatment to the final treatment, whereas no significant change was seen 
in the placebo group.
The authors went on to analyze the long term effect of these repetitive 
SPG blocks with bupivacaine in the second part of their study (11). They 
reassessed patients at 1 month and 6 months post active treatment and 
they found a sustained reduction of headache days along with an 
improvement in functional assessment in the treatment group.
Another catheter used to deliver medication topically to the region of the 
SPG is the Sphenocath. Binfalah et al (2018) reported on their open, 
uncontrolled, retrospective study of SPG blocks using Sphenocath for 
acute migraine (5). They enrolled 55 patients and delivered 2ml of 2% 
lidocaine to the region of the SPG bilaterally. Adverse events reported 
were mild, including transient throat numbness (100%), nausea (10.9%), 
dizziness (10.9%), vomiting (1.8%), nasal discomfort (18.2%), and 
worsening of preexisting headache (1.8%). These side effects were 
transient and lasted less than 24 hours. Headache freedom at 15 mins 
was 70.9%, at 2 hours was 78% and at 24 hours was 70.4%.
The Sphenocath is the device we have used in the UCSF Headache Center 
for more than 2 years with no significant side effect or complication 
experienced and with patients reporting relief. We routinely use all of the 
medications studied (lidocaine, bupivacaine and ropivacaine). The 
selection is usually based on provider preference or intuition since there 
is no evidence to guide the choice.
f.
References
1. Goadsby PJ, Zagami AS, Lambert GA. Neural processing of craniovascular 
pain. Headache. 1991; 31:365-370
2. Piagkou M, Demesticha T, Troupis T, Vlasis K, Skandalakis P, Makri A, 
Mazarakis A, Lappas D, Piagkos G, Johnson EO. The pterygopalatine 
ganglion and its role in various pain syndromes: From anatomy to clinical 
practice. Pain Pract 2011; 12:399-412


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3. Robbins MS, Robertson CE, Kaplan E, Ailani J, Charleston L, Kuruvilla D7, 
Blumenfeld A, Berliner R, Rosen NL, Duarte R, Vidwan J,Halker RB, Gill N, 
Ashkenazi A. The Sphenopalatine Ganglion: Anatomy, Pathophysiology, 
and Therapeutic Targeting in Headache. Headache. 2016 Feb;56(2):240-
58.
4. Mehta D, Leary MC, et al. The Effect of Regional Anesthetic 
Sphenopalatine Ganglion Block on Self-Reported Pain in Patients With 
Status Migrainosus. Headache. 2018 Jul 25
5. Binfalah M, Alghawi E, Shosha E, Alhilly A, Bakhiet M. Sphenopalatine 
Ganglion Block for the Treatment of Acute Migraine Headache. Pain Res 
Treat. 2018 May 7;2018:2516953
6. Mojica J, Mo B, Ng A. Sphenopalatine Ganglion Block in the Management 
of Chronic Headaches. Curr Pain Headache Rep. 2017 Jun;21(6)
7. Cady R., Saper J., Dexter K., Manley H. R. A double-blind, placebo-
controlled study of repetitive transnasal sphenopalatine ganglion 
blockade with Tx360® as acute treatment for chronic 
migraine. 2015;55(1)
8. Klein RN, Burk DT, Chase PF. Anatomically and physiologically based 
guidelines for use of the sphenopalatine ganglion block versus the 
stellate ganglion block to reduce atypical facial pain. Cranio. 2001;19:48–
55.
9. Kittrelle JP, Grouse DS,Seybold ME. Cluster headache. Local anesthetic 
abortive agents. Arch Neurol.1985;42:496–498.
10. Candido K. D., Massey S. T., Sauer R., Darabad R. R., Knezevic N. N. A 
novel revision to the classical transnasal topical sphenopalatine ganglion 
block for the treatment of headache and facial pain. 2013;16(6):E769–
E778.
11. Cady RK, Saper J, Dexter K, Cady RJ, Manley HR. Long-term efficacy of a 
double-blind, placebo-controlled, randomized study for repetitive 
sphenopalatine blockade with bupivacaine vs. saline with the Tx360 
device for treatment of chronic migraine. Headache. 2015 Apr;55(4):529-
42. 
12. Sluder G. Lower half headache (neuralgic) of nasal origin. JAMA. 
1922;79:1898–1899
13. Maizels M, Geiger AM. Intranasal lidocaine for migraine: a randomized 
trial and open-label follow-up. Headache 1999 Nov-Dec;39(10):764.
14. Blanda M, Rench T, Gerson LW, Weigand JV. Intranasal lidocaine for the 
treatment of migraine headache: a randomized, controlled trial. Acad 
Emerg Med. 2001 Apr;8(4):337-42.
15. Avcu N, Doğan NÖ,  Pekdemir M, Yaka E, Yılmaz S, Alyeşil C, Akalın LE. 
Intranasal Lidocaine in Acute Treatment of Migraine: A Randomized 
Controlled Trial. Ann Emerg Med. 2017 Jun;69(6):743-751.


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16. Kudrow L., Kudrow D. B., Sandweiss J. H. Rapid and Sustained Relief of 
Migraine Attacks With Intranasal Lidocaine: Preliminary 
Findings. 1995;35(2):79–82.
3. Procedure
UCSF Headache Center patients with chronic migraine who are identified 
by their treating physician to be a candidate for SPG block, and who meet 
inclusion criteria will offered enrollment in the study.
After the study risks have been explained and consent and HIPAA have 
been documented, the patient will be randomized to receive active drug 
or placebo using the FDA cleared medication delivery device, 
SphenoCath. This device is a needleless nasal topical applicator.  The 
small flexible catheter is introduced through the nares and delivers 
medication non-invasively to the region of the SPG.
For those patients who wish to enroll, they will be randomized in 1:1:1:1 
fashion in blocks to receive of the four study liquids given in three 
treatments spaced two to four months apart.
a.
Study drugs : bilateral nasal applications via Sphenocath (each consisting of 0.5 
cc of liquid per nostril) of the following: 
i.
Lidocaine 2% OR
ii. Bupivacaine 0.25% OR
iii. Ropivacaine  0.5% OR
iv. Normal Saline
b. Inclusion and exclusion criteria 
Inclusion Criteria
1.      Age 18 years or more at time of consent 
2.      Current patients in the UCSF Headache Center eligible to 
receive SPG blocks for migraine and would otherwise receive 
treatment clinically
3.      Ability to provide consent for the research study 
Exclusion Criteria
1.      Pregnant or breast feeding within 4 weeks of enrollment


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2.      Inability to communicate with the study team
3.      Patients who cannot read and understand English
4.      Deemed unsuitable for enrollment in study by the 
investigator
5.      Allergy to local anesthetics or saline
c.
Recruitment and Consent
The patient will come to the UCSF Headache Center for their regular clinic 
appointment. 
During this visit, the study team member will describe the research study and if 
they are interested in participating, the patient will have time to read through 
the consent form and clarify any questions that the patient may have regarding 
the study.  
Once the patient reads and understands the Informed Consent From, eligibility 
will be determined by the study physician based on medical history and study 
criteria. 
After signing the consent and HIPPA, they will be randomized to their study 
assignment.
d. Risks and Benefits 
As part of the consent process, participants will be told that when topical 
anesthetics are used in the nose, mouth, or throat, it may cause decrease in local 
sensation for a few minutes. Participants will be told to be mindful when eating 
or drinking any foods or liquids in the hour after receiving treatment. They will 
be informed that they may experience short lasting dizziness or lightheadedness 
which is exceedingly rare in our experience but reported in previous studies. 
The risk of allergies will be discussed, and all current medications and health 
conditions will be considered by the investigators before offering participation to 
patients.
Randomization and placebo risks will be described to the participant during the 
consent process.
e.
Data collection 


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The data collected at each study visit will be the frequency and intensity of 
migraine headaches during the interval period. Data will be stored in HIPAA 
compliant fashion. 
Chi square will be used to analyze to determine if there is a significant statistical 
difference among the groups.
After the next routine clinic visit post study period, we will compare mean 
number of headache days per month of mild, moderate and severe headache 
post treatment to the baseline collected prior to first SPG block.
f.
Safety monitoring
Although there is safety data for the use of anesthetic nasal blocks, and a DSMB 
is not required, safety will be carefully monitored throughout this study.
There is no planned interim analysis.  Participants may be removed from the 
study if it is in their best interest and it will be up to the determination of the PI, 
or participant.
Any serious adverse events will be communicated to the IRB, in accordance with 
their guidelines.
All serious and non-serious adverse events will be collected in an adverse event 
reporting form. 
In accordance with the standard operating procedures and policies of the local 
Institutional Review Board (IRB), the site investigator will report SAEs to the IRB 
per UCSF IRB guidelines. 
As part of the participant's visits, we will ask the patient about frequency and 
intensity of their headaches between visits (and review their standard clinic 
headache diary). Home medications along with any new medical problems will be 
reviewed with the participant before receiving the study treatment.