Clinical trial NCT03865940
Conditions: Trigeminal Neuralgia
Sponsor: Vanderbilt University Medical Center
Start date: 2019-11-04; Completion date: 2024-01-31
Enrollment: 37 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
A phenome-wide association study (PheWAS) identified an association between a loss of function variant in the human alpha 2B adrenergic receptor gene and trigeminal nerve disorders. Guanfacine is the oldest alpha-2 adrenergic agonist in clinical use and is approved for hypertension and attention deficit hyperactivity disorder. We hypothesize that guanfacine will be an effective adjunct to lidocaine for the treatment of neuropathic pain by enhancing and prolonging pain relief due to its activation of alpha-2 adrenergic receptors. The objectives of the study will be to evaluate the efficacy and safety of guanfacine in combination with lidocaine for trigeminal nerve block procedures for pain management in trigeminal neuralgia patients. This study will evaluate the efficacy of guanfacine in reducing acute pain and extending duration of pain relief when delivered in combination with lidocaine as a trigeminal nerve block, measured by Visual Analog Scale (VAS) data collected at specific time points after each injection.

Detailed description:

Arms: arm 1: Trigeminal nerve block will be performed with injection of 6 mL of 1% lidocaine (Day 1).

Patient will return between Day 15-28 and trigeminal nerve block will be performed with injection of 6 mL of 1% lidocaine + 250 mcg guanfacine. arm 2: Trigeminal nerve block will be performed with injection of 6 mL of 1% lidocaine + 250 mcg guanfacine (Day 1).

Patient will return between Day 15-28 and trigeminal nerve block will be performed with injection of 6 mL of 1% lidocaine.
Interventions: intervention 1: Lidocaine intervention 2: Guanfacine
Intervention descriptions: intervention 1: 6 mL of 1% lidocaine intervention 2: 250 mcg

Protocol documents:
Prot_SAP_001.pdf: 
Last updated: 03/07/2022 
 
1 
 
A RANDOMIZED DOUBLE-BLIND 2-WAY CROSSOVER TRIAL TO 
ASSESS 
THE 
EFFICACY 
OF 
GUANFACINE 
AND 
LIDOCAINE 
COMBINATION VERSUS LIDOCAINE ALONE IN TRIGEMINAL NERVE 
BLOCK FOR PAIN MANAGEMENT IN PAINFUL TRIGEMINAL 
NEUROPATHY PATIENTS 
 
 
Short Title: Efficacy of Guanfacine and Lidocaine combination in Painful 
Trigeminal Neuropathy Pain Management 
 
 
 
Principle Investigator(s): 
David A Edwards, MD, PhD 
Assistant Professor 
Department of Anesthesiology, Neurological Surgery 
Vanderbilt University Medical Center 
 
Tigran Kesayan, MD 
Department of Neurology 
Vanderbilt University Medical Center 
 
 
 
 
 
 


Last updated: 03/07/2022 
 
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SPONSOR AND STUDY SITE  
Vanderbilt University Medical Center 
 
 
TABLE OF CONTENTS 
 
1. Study Objective and Background 
2. Study Design 
3. Drug Product 
4. Enrollment and Informed Consent 
5. Study Procedures 
6. Risks 
7. Reporting of Adverse Events or Unanticipated Problems Involving Risk to Participants or Others 
8. Study Withdrawal/Discontinuation 
9. Statistical Considerations 
10. Privacy/Confidentiality Issues 
11. References 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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1.0 STUDY OBJECTIVE AND BACKGROUND 
 
Study Objective: 
The objectives of this study are to evaluate, in trigeminal nerve block procedures for painful trigeminal 
neuropathy adult patients between 18 and 80 years of age, 
1. The efficacy of guanfacine in combination with lidocaine compared to lidocaine alone in extending the 
pain relief duration. 
2. The safety and tolerability of a single dose of guanfacine in combination with lidocaine compared to 
lidocaine alone. 
 
Background: 
Painful trigeminal neuropathy is a severely painful condition affecting cranial nerve V (trigeminal nerve) that 
transmits sensation from the face. Painful trigeminal neuropathy affects one or more branches of the trigeminal 
nerve, most often the second (V2, maxillary) or third (V3, mandibular) division. The latest classification (ICHD-
3) by the International Headache Society (IHS) distinguishes trigeminal nerve pain into trigeminal neuralgia and 
painful trigeminal neuropathy.1 Classical trigeminal neuralgia includes cases that develop idiopathically or 
secondary to neurovascular compression.1 Painful trigeminal neuropathy is caused by structural abnormalities or 
neural damage rather than vascular compression. Common causes of painful trigeminal neuropathy include 
multiple sclerosis, tumors, acute herpes zoster, post-chemotherapy neuritis, post-radiation therapy neuritis, and 
space occupying abnormalities. The pain associated with painful trigeminal neuropathy is highly variable in 
quality and intensity.1 Painful trigeminal neuropathy is characterized by continuous or near-continuous facial pain 
often described subjectively as burning, squeezing, electrical, or likened to pins and needles.  
 
The current treatment strategy for trigeminal neuralgia and painful trigeminal neuropathy includes the use of 
neuropathic pain medications (carbamazepine, oxcarbazepine, gabapentin, lamotrigine) and interventional 
procedures ranging from conservative local blocks to more invasive ablative procedures.2–5 Traditionally, 
anticonvulsant and antidepressant medications are used to raise the threshold for neural signaling and reduce the 
severity of neuropathic pain sensed by the patient. Acute and chronic neuropathic pain treatment with these classes 
of medications is often insufficient, and opioids are added with the understanding of their accompanying risks 
and decreasing long-term benefits. Likewise, there are no supportive studies of chronic opioid use for functional 
improvement of trigeminal nerve pain.  Medical management using neuropathic pain medications remains first 
line treatment for most patients, and progression to surgical or interventional management is not uncommon when 
standard medical therapy fails.6,7 The decision to perform interventional or surgical procedures are based on many 
factors, including the patient’s age, their overall health and ability to tolerate the procedure, the duration and 
intensity of pain and its impact on quality of life, and on patient preference.8 Interventional procedures offered to 
patients with intractable trigeminal nerve pain often begin with diagnostic regional block with local anesthetic to 
ensure peripheral treatment of first-order neurons will adequately relieve the patient’s pain. Further subsequent, 
standard treatments include repeat regional blocks with addition of adjunctive medications (i.e. steroids, 
clonidine, or botulinum toxin), or progression to trigeminal nerve ablation via radio-frequency or balloon 
compression, or radiotherapy.   
 
Trigeminal nerve block using local anesthetic with or without adjuvants have been effective in relieving pain 
temporarily in some trigeminal neuralgia patients.8–12 2% lidocaine perineural injection (2-4 ml) in combination 
with neuropathic pain medications has been shown to be safe and effective in reducing pain, lowering the 
frequency of pain attacks, and reported improvement in the quality of life in classical trigeminal neuralgia 
patients.13 High concentration (10% lidocaine) perineural injection with no adjuvant has been shown to be safe 


Last updated: 03/07/2022 
 
4 
 
and effective in reducing pain in certain trigeminal neuralgia patients.8 After these blocks, pain often returns to 
previous levels of severity. The potential for more durable benefit from interventional blocks is, therefore, an 
unmet medical need.  Importantly, adjuvants in combination with lidocaine, such as clonidine or dexamethasone, 
or other steroids have previously been shown to extend the duration of the block in other regional anesthesia 
techniques.14,15  The proposed therapeutic approach is ultimately intended to generate durable relief of neuropathic 
pain without the potential side effects of steroids. 
 
Alpha-2-adrenergic receptor function in managing pain 
The alpha-2 adrenoreceptor has important roles in signaling within and between both the peripheral and central 
nervous systems. Stimulation of the alpha-2 adrenoreceptor suppresses calcium entry into the nerve terminal; it 
has been postulated that this dynamic is responsible for its inhibitory effect on secretion of neurotransmitters, 
leading to interruption of the propagation of pain signals.16 Both central and peripheral alpha-2 adrenoreceptors 
are proposed to mediate interruption of pain signaling by this mechanism.16 In humans, both the alpha 2A and 2B 
subtypes are expressed in the spinal cord and have been shown to be involved in antinociceptive activity.17 Alpha-
2 adrenergic agonists mitigate postoperative neuropathic pain in rats.18–21  
 
Alpha-2 adrenergic agonists such as clonidine and dexmedetomidine have been successfully used as adjuvants to 
local anesthetics to extend by several hours, regional blocks used for surgical analgesia or acute and chronic pain 
treatment.14 Clonidine (30 to 300 µg) is a well-known adjuvant for extending and enhancing the effect of local 
anesthetics.15 Dexmedetomidine dose-dependently (4.5 to 13.5µg) enhances the local anesthetic action of 
lidocaine in inferior alveolar nerve blocks (IANB).22 Clonidine (75 µg) with (10 ml) lidocaine, bupivacaine, and 
fentanyl has been used in trigeminal nerve block to manage pain in  trigeminal neuralgia patients without 
significant adverse events.23 
 
Guanfacine is the oldest alpha-2 adrenergic agonist in clinical use in this class.24 Of the alpha-2 agonists, 
guanfacine has the lowest rate of sedation.25 Guanfacine is currently approved in tablet form for the treatment of 
hypertension (1 to 2 mg)  and Attention Deficit Hyperactivity Disorder (1 to 4 mg). Guanfacine is readily absorbed 
with around 80% oral bioavailability and has an elimination half-life of ~17 h with renal excretion accounting for 
~50%.26 Guanfacine has been shown to have similar in vitro potency as clonidine to inhibit conduction in rat 
sciatic nerve fibers.27 Intrathecal guanfacine has a similar antinociceptive effect as that of intrathecal clonidine in 
a goat model.28 Guanfacine showed longer antinociceptive effect in comparison to clonidine (8 h vs. 5 h) due to 
slower elimination of guanfacine from spinal cord tissue. In a rat model, intrathecal guanfacine has shown anti-
nociceptive effect for greater than 18 h (both 25 mcg and 50 mcg) in comparison to clonidine injection (50 mcg) 
which declined to baseline within 4 h.29 This study also reported a lower rate of elimination of guanfacine from 
spinal cord tissue compared to clonidine. Highly concentrated guanfacine (75 mcg in 15 µl saline) solution 
administered through an intrathecal route has been shown to be nontoxic in the subarachnoid space, establishing 
the safe use of guanfacine for perineural blockade.30 Guanfacine as studied in animals and used in humans has a 
safe risk profile, suggesting that repurposing it for other indications. Guanfacine has the potential to be developed 
as a safe, non-opioid, analgesic for acute and chronic debilitating pain. Guanfacine in combination with 1% 
lidocaine is expected to be safe and to provide an extended duration of pain relief in painful trigeminal neuropathy 
patients who are not able to obtain pain relief from standard neuropathic pain medication. 
 
PheWAS data indicating the role of the alpha-2-adrenergic receptor in trigeminal nerve pain 
BioVU is a large repository of de-identified DNA samples that Vanderbilt University Medical Center (VUMC) 
has cataloged for >10 years from what otherwise would have been excess, discarded patient blood samples 
collected during routine clinical testing. Biospecimens within BioVU are linked to corresponding longitudinal 
clinical and demographic data derived from the Synthetic Derivative, our de-identified database of EMRs.31–33 


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Phenome-wide association studies (PheWAS) is a systematic and efficient approach to discover novel disease-
variant associations and pleiotropy using BioVU, a centralized resource for investigating genotype-phenotype 
associations.34  It is the comprehensive and diverse nature of the diagnostic information within EMRs that enables 
PheWAS.  PheWAS not only replicates known genetic-phenotypic associations but also reveals new phenotypic 
associations with genetic variants, enhancing analyses of the genomic basis of human diseases and providing 
genetic support for drug discovery and drug repurposing efforts.35–38 
 
Using PheWAS data we were able to identify a potentially use of guanfacine in treating trigeminal nerve pain. 
Genetic data from BioVU show that patients with a variant alpha 2B subtype receptor also have an increased 
likelihood of being diagnosed with trigeminal nerve disorders.  
 
 
2.0 
STUDY DESIGN 
 
Primary Hypothesis:  
Due to its different but relevant mechanism of action, guanfacine will be an effective adjunct to lidocaine in 
trigeminal nerve block for the treatment of painful trigeminal neuropathy by enhancing and prolonging pain relief 
compared to lidocaine alone. 
 
Endpoints 
The following endpoints will be measured to evaluate the exploratory objectives of the study assessing guanfacine 
and lidocaine in combination compared to lidocaine alone, in pain management in the painful trigeminal 
neuropathy patient. 
• Primary endpoint: time to return to baseline pain (VAS) measurement after treatment with guanfacine as 
adjuvant to 1% lidocaine compared to 1% lidocaine alone 
• Safety endpoint: comparable side effect profile of combination product compared to lidocaine alone on 
relevant adverse event measures: sedation, local site reaction, confusion 
• Secondary endpoint: pain intensity after treatment to be measured throughout the follow-up periods on a 
visual analog scale (VAS) 
• Secondary endpoint: quality of life after treatment to be measured using PROMIS Global Health -10 SF 
during the follow-up periods 
• Secondary endpoint: frequency of acute trigeminal nerve pain attacks during the follow-up periods 
• Secondary endpoint: total amount of rescue medications (opioid and non-opioid analgesics) for pain 
management during the follow-up periods  
• Secondary endpoint: time to first rescue medication during the follow-up periods 
 
Experimental Design 
The trial is designed as a single-center, randomized, double-blind, controlle, 2x2 crossover pilot study with two 
arms: study drug (guanfacine and lidocaine combination) and active control (lidocaine alone). The target sample 
size is 30 study drug vs. 30 active control. 
 
Not all participants that are randomized and initiate the first arm of the trial will necessarily complete both arms 
of the crossover trial. Based on previous experience, initiating the first arm of the cross over trial in 40 participants 
should be sufficient reach the full sample size (30 study drug vs. 30 active control). The trial will be complete 
and enrollment will cease upon reaching the full proposed sample size (30 study drug vs. 30 active control) .  


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6 
 
 
Approximately 80 patients meeting preliminary enrollment criteria will be consented for screening with the goal 
of roughly half being eligible to randomize and begin participation in the trial. 
 
Inclusion Criteria 
• Adults between 18 and 80 years of age 
• Ability to understand and read English 
• History of painful trigeminal neuropathy with persistent background facial pain severity > 5/10 on VAS 
• Experience pain with a score of greater than 5 on a 0-10 scale (VAS) in the previous 24 hours before 
procedural treatment and at the time of procedural treatment  
• Eligible for trigeminal nerve block procedure and have not had a trigeminal nerve block procedure for pain 
management prior to enrollment in the current study 
• Women of childbearing potential to provide agreement to use 2 forms of birth control while in the study 
• Able to provide informed consent 
 
Exclusion Criteria 
• Presence of a significant structural lesion (e.g., tumor) as the cause of pain as shown in at least one 
neuroimaging study. 
• Current diagnosis of fibromyalgia, temporomandibular disorders (TMD), odontogenic pain or other 
orofacial pain deemed unrelated to the trigeminal nerve as the origin. 
• Allergy or any other hypersensitivity reactions to guanfacine or lidocaine or local anesthetic of the amide 
type, or to both iodinated contrast and gadolinium contrast. 
• Females who are pregnant or breastfeeding and/or plan to become pregnant or to breastfeed during study 
participation. 
• Inappropriately positive illicit drug test.  
• Participation in another investigational drug study within 30 days before randomization. 
• Inability to understand the requirements of the study, inability to abide by the study restrictions, inability to 
fill out the questionnaires, or inability to return for the required treatments. 
• Any clinically significant medical or surgical condition that in the investigator’s opinion could interfere with 
the administration of study drug, interpretation of study results, or compromise the safety or well-being of the 
subject (i.e. infection, unable to stop anticoagulants). 
• No reliable access to telephone service to allow for contact with study personnel. 
 
 
3.0 
DRUG PRODUCTS 
 
Study drug: Lidocaine 1% PF vials will be purchased from Pfizer. API grade guanfacine will be purchased from 
Procos S.p.A., and Vanderbilt University Medical Center’s Investigational Drug Service will compound and 
dispense a 10 ml sterile syringe with a sterile locking syringe cap containing 6 ml 1% lidocaine with 250 mcg 
guanfacine (see Appendix A for mixing instructions). 
 
Active control: The active control drug (6 ml 1% lidocaine sterile injection) will be dispensed by VUMC’s 
Investigational Drug Service and will be identical in appearance to the study drug. 
 
Mode of administration: Trigeminal nerve block procedure 


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7 
 
Trigeminal nerve block will occur with the patient supine in the procedure suite. Based upon landmark and 
fluoroscopic image, the needle insertion site will be located and infiltrated with 1ml of 1% lidocaine. A 22-gauge 
stimuplex needle will be advanced under fluoroscopic guidance to the pterygoid fossa. Active stimulation at 0.75 
mV will be used to confirm needle tip approaching the V2 maxillary branch of the trigeminal nerve and reduced 
to 0.3mV upon patient sensation. After confirming that the needle tip is in position with no sensation felt by the 
patient at <0.3mV, and after negative aspiration for blood or cerebral spinal fluid (CSF), 0.25ml of iodinated 
contrast (Omnipaque 300) or gadolinium-based contrast agent (Omniscan) if allergic to iodinated contrast will be 
injected under digital subtraction fluoroscopy to ensure no vascular uptake. If vascular uptake occurs, the needle 
tip will be adjusted, and tested again for vascular uptake. After confirmation of the needle placement, 3ml of the 
study drug or active control will be delivered. The needle will be retracted and angled toward the V3 mandibular 
branch of the trigeminal nerve and confirmed in the same method with fluoroscopy and stimulation as above. 
After confirmation of needle placement, the remaining 3ml of the study drug or active control will be deposited. 
The needle will then be removed. The patient will be taken to the recovery room and monitored for 60 minutes.  
 
 
4.0 
ENROLLMENT AND INFORMED CONSENT 
 
The study will be discussed with patients identified as potential candidates by primary criteria (above 
inclusion/exclusion listing) to determine suitability and willingness to participate in the study. Study staff will 
provide participants the opportunity to consent to participate. Study staff will inform participants that participation 
is voluntary, and if they enroll, they may withdraw from the study at any time, for any reason. Participants will 
be given ample opportunity to ask questions and will have their questions answered.   
 
MyResearchAtVanderbilt (MRAV) is a participant repository recruitment tool available to Vanderbilt researchers 
that reaches over 18,000 My Health at Vanderbilt users that have previously confirmed they would like to be 
contacted directly for research. This repository provides investigators a forum for advertising to volunteers for a 
specific study. Email notifications are limited to IRB approved language, describe study specifics and provide 
contact information. To utilize this initiative, investigators complete a MRAV Access Request that is reviewed to 
ensure the recruitment tool and requested number of contacts are appropriate. To facilitate engagement and inform 
this pool of patients that they be contacted about study participation, the Study Coordinator will send an email 
approved by the IRB and MRAV study team. 
 
Research Notifications Distribution List:  Researchers can provide potential participants information about their 
study using the Research Notification Distribution List. This is a recruitment tool  available to Vanderbilt 
researchers that reaches over 18,500 Vanderbilt faculty and staff, as well as some members of the Middle 
Tennessee community To facilitate engagement and inform this pool of patients that they be contacted about 
study participation, the Study Coordinator will send an email approved by the IRB. 
 
The study will utilize EHR reports to identify and contact participants using VICTR's EHR Recruitment tool(s), 
including My Health at Vanderbilt mass Direct-to-Patient messaging and custom Reporting Workbench Report 
to identify potential participants.  
 
Reporting Workbench (RWB) Reports are available/viewable in eStar. These reports are developed using real-
time data and can be customized to meet study-specific inclusion/exclusion criteria. Research team members with 
eStar access and access to the Report Groups can view/run the reports as frequently as needed. While the report 
is generally limited to certain variables, it provides easy access to a patient's record for additional screening and 
confirmation of eligibility. A custom RWB report will be utilized to identify potential participants. The report 
will filter on study inclusion/exclusion criteria computable in the EHR and will display variables requested by the 


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8 
 
study team. Additional variables used to filter the cohort include for mass messaging include: Research OK to 
Contact status, MHAV account activation/message status. 
 
My Health at Vanderbilt (MHAV) Mass Direct-to-Patient messaging uses the MHAV patient portal to message a 
predefined cohort of patients who meet certain study-specific inclusion/exclusion criteria, have explicitly said 
OK to Contact for research, and have an active MHAV account. The IRB-approved MHAV mass messages are 
sent by the VICTR EHR Recruitment Support Team, not the study team.Potential participants who have an 
explicit OK to Contact documented in eStar will receive the following message based on the patient's MHAV 
notification preferences. If email and/or text notifications for research are not checked, the study information will 
simply appear on their research studies page in MHAV.  
 
5.0 
STUDY PROCEDURE 
 
The study is a single center, randomized, double-blind, 2 x 2 crossover pilot study with two arms; study drug 
(guanfacine and lidocaine combination) and active control (lidocaine alone). Adult participants between 18 and 
80 years of age who have been diagnosed with painful trigeminal neuropathy will be consented for the study. The 
study includes three visits; an initial visit for evaluation, consent, and baseline surveys followed by two procedural 
visits. After each procedural visit data will be collected for 14 days. Participants will be randomized in permuted 
pairs (to ensure balance after every second enrollment) to receive either study drug (guanfacine and lidocaine 
combination) or active control (lidocaine alone) for the first nerve block procedure. Following the first procedural 
visit and 14-day follow up period, the study team will assess inclusion and exclusion criteria and (if eligible) 
schedule the second procedural visit.  


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9 
 
 
#:    Collected every 30 minutes for 8 hours by text message (REDCap) or patient diary 
%:  Collected daily for up to 28 days by text message (REDCap) or patient diary 
$:    Collected weekly for up to 4 weeks by study nurse phone call 
*:    If pain score >5 
+:    Review recent imagining, if not available then order as standard of care 
^:     Order 12-lead ECG as standard of care if one not available within 2 months of screening visit 
Assessment 
Study Visit 1: 
Consent and 
screening 
(Day -15 to 0) 
Study Visit 2:  
Procedure 1 
(Day 1) 
Follow-up period 1 
(Day 2-14) 
Study Visit 3: 
Procedure 2 
(≥15 days after 
procedure 1) 
Follow-up period 2 
(14 days after 
procedure 2) 
Administrative Procedures 
Eligibility Review  
X 
X 
 
X 
 
Informed Consent 
X 
 
 
 
 
Demographics 
X 
 
 
 
 
Pain History 
X 
 
 
 
 
Baseline Pain 
X 
X 
X 
X 
X 
Medical History 
X 
 
 
 
 
Concomitant Medications 
X 
X 
 
X 
 
Surgical/ Past Treatments History 
X 
 
 
 
 
Verbal Pregnancy Screen 
X 
 
 
 
 
PROMIS Global 10- SF 
X 
X 
X $ 
X 
X $ 
Pain Interference 
X 
X 
 
X 
 
Pain Intensity (VAS Score) 
X 
X # 
X % 
X # 
X 
Frequency of Attacks 
X 
X 
X $ 
X 
X $ 
Rescue Medications 
 
X % 
X % 
X % 
X 
Randomization 
X 
 
 
 
 
Clinical Procedures/ Assessments 
Physical Exam (general) 
X 
X 
 
X 
 
Physical Exam (pain) 
X 
 
 
 
 
Vitals (HR, RR, Temp, BP) 
X 
X 
 
X 
 
Height/ Weight 
X 
 
 
 
 
12-Lead ECG ^ 
X 
 
 
 
 
Continuous ECG monitoring 
 
X 
 
X 
 
Nerve Block Administration 
 
X 
 
X * 
 
Imaging MRI/ CT report + 
X 
 
 
 
 
Adverse Events 
 
X 
X 
X 
X 
Laboratory Procedures 
Urine Pregnancy Test 
 
X 
 
X 
 
Urine Drug Screen 
X 
 
 
 
 


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10 
 
Study Visit 1:  Consent and Screening (Day -15 to Day 0) 
Patients with facial pain will be evaluated in clinic; those deemed to have a diagnosis of painful trigeminal 
neuropathy will be considered for enrollment. Informed consent will be obtained prior to collecting data. Those 
patients that meet eligibility (inclusion/exclusion criteria outlined above) will be introduced to the study. 
Consented patients will become enrolled as study participants and will complete baseline measurement prior to 
randomization. Baseline data that will be collected includes demographics (name, age, sex), physical examination; 
heart rate and rhythm, blood pressure; comorbid health conditions and prior surgeries or treatments; current and 
past medications within 6 months. Dr. Edwards will order an EKG if the participant has not had one within the 
past 2 months prior to the visit, as part of standard care. The targeted pain history will include pain duration, 
frequency of exacerbations, location, radiation, severity (VAS), quality, instigating event, exacerbations, 
alleviations, pain treatment frequency and duration of use (non-medical and medical treatments) and changes in 
pain over time. The targeted pain physical exam will include assessment of light touch test for allodynia and 
pinprick test for hyperalgesia of the trigeminal dermatome V1-3 regions of the face.  Standard practice prior to 
trigeminal nerve block is to review recent MRI or CT imaging to ensure safety of needle approach to target 
location. If no recent imaging exists, this will be ordered as part of standard care prior to nerve block. Participants 
will be asked if there is a possibility they are pregnant. Women of childbearing potential will be educated on birth 
control methods and will agree to 2 methods of birth control that they will plan to use during the study period 
(abstinence is an appropriate method). A urine drug screen for illicit use of controlled substances will be obtained. 
Patient-reported outcome forms to be completed include the PROMIS Global-10 SF and Pain Interference forms. 
Current and average 24-hour pain (VAS) before procedure will also be recorded. Assessments will be recorded 
according to the patient’s preference, either on paper or via electronic forms using REDCap. All data will be 
entered into REDCap. 
 
Study Visit 2: Procedure 1 (Day 1) 
Participants will be asked to record their pain intensity, 24- hour VAS and current VAS, before the procedure to 
establish a baseline pain score. Other data will be collected for secondary measures: frequency of pain attacks, 
basal and breakthrough opioid and non-opioid analgesic frequency and dose.  Overall quality of life (PROMIS 
Global-10 short form) will be assessed.39 Women of childbearing potential will undergo a urine pregnancy test 
prior to receiving the nerve block.  
 
First trigeminal nerve block procedure: Participant will receive either study drug (guanfacine and lidocaine 
combination) or active control (lidocaine alone) for the trigeminal nerve block based on randomization. 
Participants will be monitored for pain intensity at 30-minute time intervals for the first 8 hours after block in 
addition to safety monitoring procedures. Participant responses will be collected at 30 minute intervals for the 
first 8 hours while in the recovery (first 60 minutes) and after discharge home, with responses allowed all the way 
until the next time point and actual time of the response being used in analysis. Assessments will be recorded 
according to the patient’s preference, either on paper or via text message) using the Twilio application linked to 
REDCap. Patients will also receive a sheet with contact information for the study nurse. 
 
First follow-up period (Day 2 to Day 14) 
Participants will be monitored once daily at approximately the same timepoint for 14 days using text message 
generated using the Twilio application or recorded on a paper diary. Participants will also be monitored for any 
use of rescue medication (analgesics) once daily. The study nurse will monitor participants once weekly for 
overall quality of life via phone call using the PROMIS global 10 SF. Participants will be instructed to contact 
the study nurse with any adverse events directly by phone.  
 
 
Study Visit 3: Procedure 2 (Day 15-28) 


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11 
 
At the end of the first follow-up period, participants will be contacted for crossover to the other arm to receive 
the second trigeminal nerve block using the alternative drug (study drug or active control), not received during 
the first nerve block. At the second study visit, participants will record 24-hour VAS and current VAS, and the 
PROMIS Global-10 Short Form to establish baseline measurement again. Women of childbearing potential will 
undergo a urine pregnancy test prior to receiving the nerve block.  
 
 If VAS < 5 on the pain scale, participants will not be eligible for second trigeminal nerve block during the visit. 
Study nurse will continue monitoring the participant’s pain intensity (daily through day 15, and weekly thereafter) 
to see if the participant pain is above 5 on the pain scale and eligible for the second block. In general, the study 
intends that participants would receive both treatments unless they experience intolerable toxicity. If a participant 
is unable or ineligible to receive second trigeminal nerve block, then the participant’s data collected during the 
first nerve block will be included in the analysis. In addition, a replacement participant will be enrolled so that 
the minimum number of 30 for each arm is reached. An intention-to-treat analysis will be done post-hoc to 
evaluate any differential progress to second block between the initial randomized groups.  
   
Second trigeminal nerve block procedure: Participant will receive second trigeminal nerve block followed by 
monitoring for pain intensity at 30-minute time intervals for the first 8 hours after block, again allowing responses 
all the way until the next time point. 
 
Second follow-up period (14 days) 
Participants will be monitored once daily at the same timepoint for 14 days using text message generated using 
the Twilio application or recorded on a paper diary. Participants will also be monitored for any use of rescue 
medication (analgesics) once daily. The study nurse will monitor participants once weekly for overall quality of 
life via phone call. Participants will be instructed to contact the study nurse with any adverse events directly by 
phone.  
 
 
 
Figure: 1. Study Schema 
 


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12 
 
 
6.0  RISKS 
 
During the consent process, study personnel will address potential discomfort and risks associated with the 
protocol. These will be included in the consent form.  
 
Based on the known common side effects of the study drugs and the trigeminal block procedure, the following 
risk associated with participation in the study are perceived as low: 
- 
Bradycardia  
- 
Hypotension 
- 
Dry Mouth 
- 
Sedation 
- 
Dizziness 
- 
Headache 
- 
Bruising, redness, itching, or swelling at the site of injection 
- 
Intravascular injection resulting in seizure or stroke 
- 
Bleeding 
- 
Increased pain 
 
In the event sedation or dizziness is observed after the procedure, standard of care practices for managing side 
effects will be performed, and the event will be documented and recorded according to the regulation.  
 
It is understood that there may be as-yet unknown or unanticipated adverse effects of this study treatment. The 
study team will continually monitor for these effects and consider altering the protocol if needed to ensure patient 
safety. Changes in the procedures of the study, as well as any change(s) in the risks and/or benefits will be 
presented to and discussed with the subjects upon approval from the appropriate regulatory bodies for 
implementation of such revision(s). 
 
Safety Monitoring: 
Patients are examined on the day of the procedure to confirm the source of pain, vital signs are stable and in 
normal range, and female patients are confirmed not-pregnant through point of care pregnancy tests. During the 
procedure continuous pulse oximetry is used to monitor oxygenation, blood pressure is obtained every 2 minutes, 
and 3-lead electrocardiogram is monitored for heart rate and rhythm. Following the procedure, patients are taken 
to the recovery room adjacent to the procedure room to be monitored for 1 hour with continuous pulse oximetry, 
blood pressure (measured every 5 minutes), and continuous ECG to ensure stable vital signs.  The patients are 
discharged home with a responsible adult after recovery.  Before, during, and after the procedure patients are 
monitored by a registered nurse skilled in the evaluation of vital signs and familiar with the procedure. Dr. 
Edwards is an Anesthesiologist and will be present for the duration of patient care.   
 
Data Monitoring: 
The PI and study coordinator will be responsible for real-time monitoring of all trial-related activities. Dr. 
Edwards will assure that the study is conducted according to Good Clinical Practice Guidelines and according to 
FDA requirements.  The study team will meet bi-weekly to review recruitment, enrollment, retention, status of 
each participant currently enrolled, adverse events.  Targets will be established for enrollment and completion 
and reviewed at each meeting where strategies will be discussed to assure that the study is on track.  Enrollment 
tables will be developed by the coordinator and project manager for review at team meetings.  Adverse and serious 
adverse events reports will be monitored in real-time by the PI, project manager, and study coordinator.  All final 


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13 
 
data will be stored on case report forms in REDCap with all source documents uploaded into REDCap then 
shredded. 
All study data, including those captured from the EHR and other hospital databases, will be transferred into the 
study database via standardized electronic case report forms (eCRFs) which will reside in a centralized REDCap 
database located on Vanderbilt’s secure servers. REDCap is a secure, web-based application for building and 
managing online databases. Vanderbilt University, with collaboration from a consortium of institutional partners, 
including the Vanderbilt Institute for Clinical and Translation Research (VICTR) Informatics Core, developed 
and manages a software toolset and workflow methodology for electronic collection and management of research 
and clinical trial data. All study data will be entered via a password protected, study unique REDCap database 
website. REDCap servers are housed in a local data center at Vanderbilt and all web-based information 
transmission is encrypted. REDCap was developed specifically around HIPAA Security guidelines and is 
recommended by both the Vanderbilt University Privacy Office and Institutional Review Board. REDCap has 
been disseminated for use locally at other institutions and currently supports more than 2,700 academic/non-profit 
consortium partners and over 657,000 research end-users (www.project-redcap.org). Data will be accessed via 
password protected and secured Web-based interface for data entry and data cleaning. REDCap contains an audit 
trail for tracking all activities within the system. 
 
To ensure data is accurately and completely collected during the study, periodic monitoring will occur by the 
Project Manager to ensure the study protocol is being followed, protocol changes have been implemented 
appropriately, data are being captured per protocol, and are accurate, complete, and current for study subjects. 
Per best practice guidelines, the monitor will compare a representative number of subject records and other 
supporting documents with the investigator’s reports. Specifically, monitoring activities will include: 
  
[1] A Technical Review annually which will consist of the Project Manager examining the quality and accuracy 
of data, regulatory documents, and other essential documents. Data quality and accuracy will be reviewed through 
a CRF data and source document review. The Project Manager will randomly select a pre-determined number of 
study participants to serve as a representative sample. Regulatory Document Review will consist of a review of 
IRB approvals, informed consents, critical documents, and protocols/amendments.  
 
[2] The Scientific Review will occur biennially and will consist of a review of the study’s organizational structure, 
patient recruitment, staff training, and quality control procedures by the Project Manager. Site monitoring 
progress reports will be submitted to the DSMB and other regulatory bodies (IRB, FDA and NIH) as requested 
and/or required. This Monitoring Plan will serve as a method for identifying systematic problems and provide a 
means in which to institute resolution and follow-up and therefore increase data quality. 
 
Any omissions and corrections to data submitted to REDCap are noted and queries are generated by the Project 
Manager or by REDCap’s automated system. Data are checked and verified by the Project Manager.  A green 
check is placed beside items that have been verified as accurate when compared to source documentation. For 
those items that are not initially verified, a query will be issued using the Data Quality Tool in REDCap. Users 
will then be able to pull up a list of queries using the Resolve Issues Application. Queries will be responded to 
directly on each respected eCRF page.  Furthermore, there is an option to upload additional documentation if 
requested by the Project Manager. Once a query has been answered, the Project Manager will review the new 
information and choose to either re-query the data point or close the query by verifying that the data point is 
complete and accurate. Once all data points on the eCRF page have been reviewed and verified as accurate, a 
green verification check will be placed at the bottom of the page and the page will be locked, to show that the 
data on the page is acceptable and ready to be signed off on by the Principal Investigator.  If a data point is revised 
after it was verified and accepted as accurate by the Project Manager then a red exclamation mark will appear 


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14 
 
beside the data point.  The Project Manager will be notified via the Data Quality Application and will have the 
option to issue a new query regarding the change or to verify the new data as accurate and complete. All queries 
will be stored in REDCap’s logging and audit trail so that all data revisions are tracked and permanently recorded 
in order to verify data accuracy.  The audit trail will contain a time stamped record of revisions and data entry 
within the database.  All data points entered for the first two patients enrolled at each site will be thoroughly 
monitored. Thereafter, specific data points that support the primary and secondary endpoints (ex. 
Inclusion/Exclusion criteria, informed consent, and randomization strata) will be thoroughly reviewed by a 
Project Manager.  20% to 100% of all additional data points will then be randomly monitored for accuracy.  
Queries will be issued no later than one month after completed eCRF pages are reviewed.  Review will be 
expedited in cases of urgent concern.  Open queries must be answered within 14 calendar days. 
All data entered into the REDCap system must come from an original source. Study coordinators will upload all 
related source documents and medical records that contain information (including Protected Health Information 
for verification purposes) used in completing the eCRFs into the secure REDCap system. If original source is 
given verbally and/or if study procedures were documented outside of the medical record, an original source 
document must be created (which includes applicable signatures and dates) that provides an accurate account of 
the information that was exchanged.  All applicable study source documentation will be uploaded into REDCap 
for monitoring purposes then shredded. 
 
7.0 
REPORTING OF ADVERSE EVENTS OR UNANTICIPATED PROBLEMS INVOLVING RISK 
TO PARTICIPANTS OR OTHERS 
 
Adverse Event 
An AE is “any untoward medical occurrence in a patient or clinical investigation subject administered a 
pharmaceutical product and which does not necessarily have a causal relationship with this treatment.” An adverse 
event can, therefore, be any unfavorable and unintended sign, symptom, or disease temporally associated with the 
use of a medicinal (investigational) product, whether or not considered related to the medicinal (investigational) 
product. 
AEs include any of the following: 
• Worsening (change in nature, severity or frequency) of conditions present at the onset of the trial 
• Subject deterioration due to the primary illness 
• Intercurrent illnesses 
• Drug interactions 
• Events related or possibly related to concomitant medications 
• Changes of vital signs, as well as significant shifts from baseline within the range of normal, which the 
Investigator considers to be clinically significant 
 
Adverse Drug Reaction 
In the pre-approval clinical experience with a new medicinal product or its new usage, particularly as the 
therapeutic dose(s) may not be established, an adverse drug reaction is defined as: 
All noxious and unintended responses to a medicinal product related to any dose should be considered adverse 
drug reactions (ADR). 
 
Unexpected Adverse Drug Reaction 
An unexpected ADR is: 
An adverse drug reaction, the nature or severity of which is not consistent with the applicable product 
information, also known as reference safety information. The reference safety information is the package insert 
of the individual drug. 


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15 
 
 
Serious Adverse Event/Serious Adverse Drug Experience 
During clinical investigations, serious AEs may occur,  if the event is suspected to be drug-related, the event may 
be significant enough to lead to important changes in the way the medicinal product is developed (e.g., change in 
dose, population, needed monitoring, consent forms). This is particularly true for reactions, which, in their most 
severe forms, threaten life or function.   
 
A serious AE (SAE) or serious adverse drug experience (SADE) is any untoward medical occurrence that: 
• Results in death 
• Is life-threatening. ‘Life-threatening” refers to an event in which the subject is at risk of death at the time 
of the event; it does not refer to an event which hypothetically might have caused death if it were more 
severe (ICH E6). 
• Requires inpatient hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability/ incapacity (as per reporter’s opinion) 
• Is a congenital anomaly/birth defect 
• Is another medically important condition.  Important medical conditions that may not result in death, be 
life-threatening or require hospitalization may be considered as SAEs or SADEs when, based upon 
appropriate medical judgment, they may jeopardize the subject or may require intervention to prevent one 
of the outcomes listed in the definition above. Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm; blood dyscrasias or convulsions that do not result 
in hospitalization; or development of drug dependency or drug abuse [Code of Federal Regulations Title 
21, Volume 5, 21CFR312.32, revised April 1, 2006]. 
 
Please note: Serious is not synonymous with severe. An event may be severe (e.g., severe headache) but still be 
of minor medical significance. Serious refers to an event that poses a threat to the subject’s life or functioning. 
 
Assigning Severity to an Adverse Event 
Mild:        Causing no limitation of usual activities,             
      the subject may experience slight discomfort. 
Moderate: Causing some limitation of usual activities,         
      the subject may experience annoying discomfort. 
Severe:     Causing inability to carry out usual activities;      
      the subject may experience intolerable discomfort or pain. 
 
Assigning Relationship of Adverse Event to Study Drug (Causality) 
The Principal Investigator will determine the relationship of each SAE to study drug (i.e., causality) by using the 
classification criteria ‘not related,' ‘possibly related’, or ‘probably related’. Descriptions of the three classification 
categories are as follows: 
 
Not Related 
Exposure to study drug has not occurred; administration of study drug and the adverse event are not reasonably 
related in time; or the SAE is considered by the Investigator to be due to a pre-existing condition, a known 
manifestation of the target disease, a recurrent condition, or is likely explained by environmental or diagnostic 
therapeutic factors or was pre-existing and did not deteriorate. 
Possibly Related 
The SAE occurred during or within a reasonable period of time after administration of the study drug, or a pre-
existing event worsened within an appropriate period of time after administration of study drug, but the SAE 


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16 
 
could be explained equally well by factors or causes other than exposure to the study drug.  This category will 
also be used if there is a lack of information, or insufficient or conflicting evidence exists for classifying the 
causality of the SAE. 
 
Probably Related 
The SAE occurred during or within a reasonable period of time after administration of the study drug or a pre-
existing event worsened within an appropriate period of time after administration of study drug, and at least one 
of the following criteria is applicable: 
• the event could not be explained by the clinical condition or history of the subject, environmental or toxic 
factors, or other diagnostic or therapeutic measures; 
• the event was an expected ADR associated with study treatment or a class-labeled drug effect; 
• the SAE subsided or disappeared after withdrawal or dose reduction of study treatment; or 
• the SAE recurred after re-exposure to study treatment. 
 
Adverse Event Recording 
Each adverse event occurring to a subject, either spontaneously revealed by the subject or observed by the 
Investigator, whether believed to be related or unrelated to the study drug, must be recorded on the AE Case 
Report Form and the subject’s file.  
 
Adverse Event Reporting 
All adverse events (AEs) recorded on the adverse event form and will be sent to the Principal Investigator (PI) 
within 72 hours of the event. AEs will be reported to the IRB according to the IRB policies and procedures. Any 
unanticipated problems involving risk to the participants or others will be discussed with the Principal Investigator 
(PI). 
 
Serious Adverse Event Reporting 
All SAEs will be recorded on the adverse event case report form and will be reported to the Principal Investigator 
within 24 hours after becoming aware of their occurrence. All SAEs will be reported to the IRB and FDA in 
accordance with applicable regulations and policies. Our procedures for reporting the serious adverse events will 
be as follows: 1. SAEs will be recorded in the patient’s study chart and reported to the Principal Investigator 
within 24 hours of the study team’s awareness of the occurrence by email or text message and will be reported to 
Vanderbilt’s IRB according to IRB policies (5 working days). The Study Coordinator will report the event within 
5 business days to the Safety Monitor who will be responsible for systematically reviewing SAEs, assigning 
causality, and evaluating relatedness of each event. The Principal Investigator will have the opportunity to review 
and agree (or not) with the Safety Monitor’s determination on each event. When the Safety Monitor suspects an 
event is study-related, he/she will have the opportunity (if he/she chooses) to access additional data in order to 
conduct appropriate safety monitoring. The Safety Monitor will determine if any necessary actions need to occur 
as result of the event in order to increase the safety of the protocol. 
 
Safety Stopping Criteria: 
The trigeminal block procedure is standard of care in the pain clinic. Expected effects of successful block include 
transient numbness, transient facial weakness including ipsilateral eyelid lag, and rare visual changes all of which 
resolve with the resolution of the effects of lidocaine over the typical course of 2 hours. Rare risks of the block 
procedure include infection, bleeding, nerve injury from the mechanical placement of the block needle. Rare risks 
of using lidocaine during the block procedure include intravascular or subdural injection resulting in transient 
unresponsiveness and/or seizure, mild sedation, bradycardia, and arrhythmias. These rare risks and side-effects 
must be differentiated from potential side-effects due to the addition of guanfacine. As all eligible patients are in 


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17 
 
clinic for diagnostic nerve block as standard of care, they will receive clinical consent to treatment for the injection 
procedure itself and necessary x-ray radiation as part of routine care.  
 
Common side-effects of daily oral use of guanfacine include dizziness, drowsiness, tiredness, low blood pressure, 
and slow heart rate. These side-effects are similar among other medications in the same class including clonidine, 
dexmedetomidine, tizanidine. Clonidine is also used as an intrathecal analgesic and as a perineural adjunctive 
injectate for regional blocks. We would expect that the side-effects of guanfacine as an adjunct to lidocaine block 
might additionally include increased dizziness, drowsiness, tiredness, low blood pressure, and slow heart rate.  If 
the level of sedation experienced by at least 20% of patients in either group is greater than anticipated either by 
severity or duration, study enrollment will be stopped and the safety monitor engaged for an interim review of 
data comparing the study groups. If oversedation is occurring in only one group, an adjustment will be made to 
maintain monitoring for more than an hour (as is standard) until complete recovery. 
 
Potential adverse events (AE) including any occurrence of the above listed procedural or medicine-related side-
effects and risks will be documented as AE’s, described and categorized as mild-, moderate-, severe- AE and 
submitted for review by the safety monitor and IRB. The PI will also submit the likelihood of the AE being 
potentially related to the use of guanfacine. Severe AEs would include the occurrence of a seizure, severe sedation 
requiring ventilation support; bradycardia, unstable arrhythmias, or hypotension requiring resuscitation (medical 
or mechanical).  The occurrence of a severe AE that is deemed study related would result in a stop of enrollment 
to report the data to the IRB, and FDA guidance would be obtained prior to study restart. 
 
 
8.0 
STUDY WITHDRAWAL/DISCONTINUATION 
 
Participants will be advised that they have the right to withdraw from the study at any point in time for any reason.  
During the study, if the participants no longer wants to participate, they will be withdrawn from the study. Contact 
information for the PI and study staff will be made available to the participant upon enrollment in the consent 
document. 
 
Subjects will be withdrawn from the study if the PI’s medical judgment is that participation places the subject at 
risk for harm. 
 
 
9.0 
STATISTICAL CONSIDERATIONS 
 
The effects of guanfacine adjuvant (intervention) versus active control on the time to return to baseline pain 
(primary) will be assessed using linear mixed-effects regression, adjusting for randomization order group and its 
interaction with the intervention/control indicator. A random intercept indexed by study participant will be used 
to account for within-participant correlation of the pre- and post-crossover measurements. The linear model 
assumptions will be assessed by examining residuals, conditional on the empirical Bayes estimates of random 
effects. If there is evidence that the linear model assumptions are violated (e.g., non-normal residuals or the very 
unlikely possibility of right censoring), alternative model formulations will be considered as necessary. The 
overall effect of intervention on the primary outcome will be tested using a two degree-of-freedom chunk test 
against the null hypothesis of no intervention main effect and no order-by-intervention interaction. The effects of 
intervention on the mean time to return to baseline will be summarized using estimates and 95% confidence 
intervals, stratified by order group. The effects of guanfacine adjuvant versus active control on secondary 
outcomes will be assessed using similar mixed-effects regression techniques as appropriate for the type of 
outcome (including proportional hazards, cumulative logit, logistic, and linear regression methods), adjusting for 


Last updated: 03/07/2022 
 
18 
 
randomization order group and its interaction with the intervention/control indicator. A random intercept indexed 
by study participant will be used to account for within-participant correlation. Quantitative and/or graphical 
regression diagnostics will be examined, and alternative model formulations will be considered as appropriate. 
Intervention effects will be tested and summarized as described above. No familywise hypotheses will be tested; 
no adjustments will be made to control any familywise type-I error probability. The type-I error rate will be fixed 
at 5%. All statistical analyses will be implemented in R (www.r-project.org; latest version) and the add-on 
package “lme4” and other packages as necessary. 
 
9.1 Statistical power and sample size. Evidence from the medical literature and expert opinion suggests that the 
mean duration of pain relief after treatment with lidocaine alone (active control group) is approximately 140 
minutes. The sample size for the proposed study was 
selected to achieve at least 80% power to detect a 20% or 
greater increase in the duration of pain relief after 
treatment with lidocaine plus guanfacine as an adjuvant 
(treatment group). This corresponds to a mean difference 
of 28 minutes. Again, although this degree of difference 
is not likely to be clinically meaningful, we are 
conducting this trial as a proof of mechanism only. If 
successful, we would pursue a modified formulation of 
guanfacine such that delivery was extended and pain 
relief duration was considerably longer. A simulation-
based power analysis was implemented using linear 
mixed-effects regression as described above. Both 
between- 
and 
within-subjects 
variability 
were 
conservatively assumed to have standard deviation 30 
minutes. Under these conditions, 30 participants will ensure approximately 90% power to detect a significant 
mean difference (28 minutes or greater in pain relief duration). Figure 2 illustrates the estimated statistical power 
for somewhat larger and smaller effect sizes (i.e., 15%, 20%, and 25% increase in pain relief duration), for a 
variety of sample sizes.  
Dropout and intent-to-treat: If VAS < 5 on the pain scale, participants will not be eligible for second trigeminal 
nerve block during the visit. Study nurse will continue monitoring the participant’s pain intensity daily (days 15-
28) to monitor when the participant pain is above 5 on the pain scale and eligible for the second block. In general, 
the study intends that participants would receive both treatments unless they experience intolerable toxicity. If a 
participant is unable or ineligible to receive second trigeminal nerve block, then the participant’s data collected 
during the first nerve block will be included in the final analysis. In addition, a replacement participant will be 
enrolled so that the minimum number of 30 for each arm is reached. An exploratory analysis will be done post-
hoc to evaluate any differential progress to second block between the initial randomized groups. Approximately 
70 people with painful trigeminal neuropathy will be evaluated at Vanderbilt University Medical Center to 
determine if they are eligible to take part in this study.  We expect to consent 70 subjects with 30 completing the 
full study. 
Although 28-70 incremental/additional minutes of pain relief would be clinically significant by itself, the study 
finding would validate the pain relief mechanism of guanfacine in the trigeminal nerve and show that enhanced 
pain relief can be achieved by the combination of drugs, and therefore extends the utility of the mechanism into 
further clinical development. 
 
 
Figure 2. Power Curves 


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19 
 
10.0 
PRIVACY/CONFIDENTIALITY ISSUES 
 
A database will be designed for this study using REDCap (Research Electronic Data Capture) tools. REDCap is 
a secure, web-based application designed to support data capture for research studies and was developed 
specifically around HIPAA-Security guidelines.  PI and study personnel are trained in HIPAA privacy 
regulations. All reasonable efforts will be made to keep a patient’s protected health information (PHI) private and 
confidential.  Participants will be identified with a study identification number.  There will be limited access to 
medical records and de-identification of all records.  Federal privacy guidelines will be followed when using or 
sharing any protected health information.  
 
Much like email, text messaging is not considered a secure form of communication.   These surveys use a third-
party service called Twilio to deliver the text messages and collect your answers.  REDCap goes to great lengths 
to ensure that text transcripts do not stay in Twilio’s records but are removed shortly after being completed and 
transferred to REDCap. This is done for privacy and security concerns –answers and phone number do not get 
permanently logged in Twilio’s computers but instead remain securely in REDCap. 
 
 
 


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20 
 
11.0 
REFERENCES 
1 
International Headache Society. 13.1.1 Classical trigeminal neuralgia. IHS Classif ICHD-3 Beta n.d. 
2 
Tuleasca C, Régis J, Sahgal A, De Salles A, Hayashi M, Ma L, et al. Stereotactic radiosurgery for 
trigeminal neuralgia: a systematic review. J Neurosurg 2018:1–25. 
https://doi.org/10.3171/2017.9.JNS17545. 
3 
Grewal SS, Kerezoudis P, Garcia O, Quinones-Hinojosa A, Reimer R, Wharen RE. Results of 
Percutaneous Balloon Compression in Trigeminal Pain Syndromes. World Neurosurg 2018;114:e892–9. 
https://doi.org/10.1016/j.wneu.2018.03.111. 
4 
Telischak NA, Heit JJ, Campos LW, Choudhri OA, Do HM, Qian X. Fluoroscopic C-Arm and CT-Guided 
Selective Radiofrequency Ablation for Trigeminal and Glossopharyngeal Facial Pain Syndromes. Pain 
Med Malden Mass 2018;19:130–41. https://doi.org/10.1093/pm/pnx088. 
5 
Di Stefano G, Truini A, Cruccu G. Current and Innovative Pharmacological Options to Treat Typical and 
Atypical Trigeminal Neuralgia. Drugs 2018. https://doi.org/10.1007/s40265-018-0964-9. 
6 
Taylor JC, Brauer S, Espir ML. Long-term treatment of trigeminal neuralgia with carbamazepine. 
Postgrad Med J 1981;57:16–8. 
7 
Killian JM. Carbamazepine in the Treatment of Neuralgia: Use and Side Effects. Arch Neurol 
1968;19:129. https://doi.org/10.1001/archneur.1968.00480020015001. 
8 
Han KR, Kim C, Chae YJ, Kim DW. Efficacy and safety of high concentration lidocaine for trigeminal 
nerve block in patients with trigeminal neuralgia. Int J Clin Pract 2008;62:248–54. 
https://doi.org/10.1111/j.1742-1241.2007.01568.x. 
9 
Choi YK, Liu J. The use of 5% lidocaine for prolonged analgesia in chronic pain patients: a new 
technique. Reg Anesth Pain Med 1998;23:96–100. 
10 Radwan IA, Saito S, Goto F. High-concentration tetracaine for the management of trigeminal neuralgia: 
quantitative assessment of sensory function after peripheral nerve block. Clin J Pain 2001;17:323–6. 
11 Goto F, Ishizaki K, Yoshikawa D, Obata H, Arii H, Terada M. The long lasting effects of peripheral nerve 
blocks for trigeminal neuralgia using a high concentration of tetracaine dissolved in bupivacaine: Pain 
1999;79:101–3. https://doi.org/10.1016/S0304-3959(98)00156-0. 
12 Stajcić Z, Juniper RP, Todorović L. Peripheral streptomycin/lidocaine injections versus lidocaine alone in 
the treatment of idiopathic trigeminal neuralgia. A double blind controlled trial. J Cranio-Maxillo-Fac 
Surg Off Publ Eur Assoc Cranio-Maxillo-Fac Surg 1990;18:243–6. 
13 Di Stani F, Ojango C, Dugoni D, Di Lorenzo L, Masala S, Delfini R, et al. Combination of 
pharmacotherapy and lidocaine analgesic block of the peripheral trigeminal branches for trigeminal 
neuralgia: a pilot study. Arq Neuropsiquiatr 2015;73:660–4. https://doi.org/10.1590/0004-282X20150077. 
14 Kirksey MA, Haskins SC, Cheng J, Liu SS. Local Anesthetic Peripheral Nerve Block Adjuvants for 
Prolongation of Analgesia: A Systematic Qualitative Review. PLOS ONE 2015;10:e0137312. 
https://doi.org/10.1371/journal.pone.0137312. 
15 Pöpping DM, Elia N, Marret E, Wenk M, Tramèr MR. Clonidine as an adjuvant to local anesthetics for 
peripheral nerve and plexus blocks: a meta-analysis of randomized trials. Anesthesiology 2009;111:406–
15. https://doi.org/10.1097/ALN.0b013e3181aae897. 
16 Gertler R, Brown HC, Mitchell DH, Silvius EN. Dexmedetomidine: a novel sedative-analgesic agent. 
Proc Bayl Univ Med Cent 2001;14:13–21. 
17 Sasson S, Unterwald EM, Kornetsky C. Potentiation of morphine analgesia by d-amphetamine. 
Psychopharmacology (Berl) 1986;90:163–5. 
18 Huang X, Deng R, Tu W, Hu Z. Dexmedetomidine reduces neuropathic pain in a rat model of skin/muscle 
incision and retraction. Asian J Surg 2017;40:35–40. https://doi.org/10.1016/j.asjsur.2015.10.009. 


Last updated: 03/07/2022 
 
21 
 
19 Farghaly HSM, Mahmoud AM, Abdel-Sater KA. Effect of dexmedetomidine and cold stress in a rat 
model of neuropathic pain: Role of interleukin-6 and tumor necrosis factor-α. Eur J Pharmacol 
2016;776:139–45. https://doi.org/10.1016/j.ejphar.2016.02.046. 
20 Murai N, Sekizawa T, Gotoh T, Watabiki T, Takahashi M, Kakimoto S, et al. Spontaneous and evoked 
pain-associated behaviors in a rat model of neuropathic pain respond differently to drugs with different 
mechanisms of action. Pharmacol Biochem Behav 2016;141:10–7. 
https://doi.org/10.1016/j.pbb.2015.11.008. 
21 Farghaly HS, Abd-Ellatief RB, Moftah MZ, Mostafa MG, Khedr EM, Kotb HI. The effects of 
dexmedetomidine alone and in combination with tramadol or amitriptyline in a neuropathic pain model. 
Pain Physician 2014;17:187–95. 
22 Ouchi K, Sugiyama K. Dexmedetomidine Dose Dependently Enhances the Local Anesthetic Action of 
Lidocaine in Inferior Alveolar Nerve Block: A Randomized Double-Blind Study. Reg Anesth Pain Med 
2016;41:348–55. https://doi.org/10.1097/AAP.0000000000000380. 
23 Naja MZ, Al-Tannir M, Naja H, Ziade MF, Zeidan A. Repeated nerve blocks with clonidine, fentanyl and 
bupivacaine for trigeminal neuralgia. Anaesthesia 2006;61:70–1. https://doi.org/10.1111/j.1365-
2044.2005.04486.x. 
24 Luttinger D, Ferrari R, Perrone MH, Haubrich DR. Pharmacological analysis of alpha-2 adrenergic 
mechanisms in nociception and ataxia. J Pharmacol Exp Ther 1985;232:883–9. 
25 Yamadera H, Ferber G, Matejcek M, Pokorny R. Electroencephalographic and psychometric assessment 
of the CNS effects of single doses of guanfacine hydrochloride (Estulic) and clonidine (Catapres). 
Neuropsychobiology 1985;14:97–107. https://doi.org/118212. 
26 Cruz MP. Guanfacine Extended-Release Tablets (Intuniv), a Nonstimulant Selective Alpha(2A)-
Adrenergic Receptor Agonist For Attention-Deficit/Hyperactivity Disorder. P T Peer-Rev J Formul 
Manag 2010;35:448–51. 
27 Butterworth JF, Strichartz GR. The alpha 2-adrenergic agonists clonidine and guanfacine produce tonic 
and phasic block of conduction in rat sciatic nerve fibers. Anesth Analg 1993;76:295–301. 
28 Smith BD, Baudendistel LJ, Gibbons JJ, Schweiss JF. A comparison of two epidural alpha 2-agonists, 
guanfacine and clonidine, in regard to duration of antinociception, and ventilatory and hemodynamic 
effects in goats. Anesth Analg 1992;74:712–8. 
29 Post C, Gordh T, Minor BG, Archer T, Freedman J. Antinociceptive effects and spinal cord tissue 
concentrations after intrathecal injection of guanfacine or clonidine into rats. Anesth Analg 1987;66:317–
24. 
30 Gordh T, Post C, Olsson Y. Evaluation of the toxicity of subarachnoid clonidine, guanfacine, and a 
substance P-antagonist on rat spinal cord and nerve roots: light and electron microscopic observations 
after chronic intrathecal administration. Anesth Analg 1986;65:1303–11. 
31 Roden DM, Pulley JM, Basford MA, Bernard GR, Clayton EW, Balser JR, et al. Development of a large-
scale de-identified DNA biobank to enable personalized medicine. Clin Pharmacol Ther 2008;84:362–9. 
https://doi.org/10.1038/clpt.2008.89. 
32 National Institutes of Health. NIH Genomic Data Sharing Policy. National Institutes of Health: Grants. 
2014. URL: http://grants.nih.gov/grants/guide/notice-files/NOT-OD-14-124.html (Accessed 27 September 
2016). 
33 Bowton E, Field JR, Wang S, Schildcrout JS, Driest SLV, Delaney JT, et al. Biobanks and Electronic 
Medical Records: Enabling Cost-Effective Research. Sci Transl Med 2014;6:234cm3–234cm3. 
https://doi.org/10.1126/scitranslmed.3008604. 
34 Denny JC, Ritchie MD, Basford MA, Pulley JM, Bastarache L, Brown-Gentry K, et al. PheWAS: 
demonstrating the feasibility of a phenome-wide scan to discover gene-disease associations. Bioinforma 
Oxf Engl 2010;26:1205–10. https://doi.org/10.1093/bioinformatics/btq126. 


Last updated: 03/07/2022 
 
22 
 
35 Denny JC, Crawford DC, Ritchie MD, Bielinski SJ, Basford MA, Bradford Y, et al. Variants near FOXE1 
are associated with hypothyroidism and other thyroid conditions: using electronic medical records for 
genome- and phenome-wide studies. Am J Hum Genet 2011;89:529–42. 
https://doi.org/10.1016/j.ajhg.2011.09.008. 
36 Hebbring SJ, Schrodi SJ, Ye Z, Zhou Z, Page D, Brilliant MH. A PheWAS approach in studying HLA-
DRB1*1501. Genes Immun 2013;14:187–91. https://doi.org/10.1038/gene.2013.2. 
37 Ritchie MD, Denny JC, Zuvich RL, Crawford DC, Schildcrout JS, Bastarache L, et al. Genome- and 
phenome-wide analyses of cardiac conduction identifies markers of arrhythmia risk. Circulation 
2013;127:1377–85. https://doi.org/10.1161/CIRCULATIONAHA.112.000604. 
38 Pulley JM, Shirey-Rice JK, Lavieri RR, Jerome RN, Zaleski NM, Aronoff DM, et al. Accelerating 
Precision Drug Development and Drug Repurposing by Leveraging Human Genetics. ASSAY Drug Dev 
Technol 2017;15:113–9. https://doi.org/10.1089/adt.2016.772. 
39 Hays RD, Bjorner JB, Revicki DA, Spritzer KL, Cella D. Development of physical and mental health 
summary scores from the patient-reported outcomes measurement information system (PROMIS) global 
items. Qual Life Res Int J Qual Life Asp Treat Care Rehabil 2009;18:873–80. 
https://doi.org/10.1007/s11136-009-9496-9. 
40 UniProt Consortium. UniProt: a hub for protein information. Nucleic Acids Res 2015;43:D204-212. 
https://doi.org/10.1093/nar/gku989. 
41 Karczewski KJ, Weisburd B, Thomas B, Solomonson M, Ruderfer DM, Kavanagh D, et al. The ExAC 
browser: displaying reference data information from over 60 000 exomes. Nucleic Acids Res 
2017;45:D840–5. https://doi.org/10.1093/nar/gkw971. 
42 Kumar P, Henikoff S, Ng PC. Predicting the effects of coding non-synonymous variants on protein 
function using the SIFT algorithm. Nat Protoc 2009;4:1073–81. https://doi.org/10.1038/nprot.2009.86. 
43 Adzhubei I, Jordan DM, Sunyaev SR. Predicting functional effect of human missense mutations using 
PolyPhen-2. Curr Protoc Hum Genet Editor Board Jonathan Haines Al 2013;Chapter 7:Unit7.20. 
https://doi.org/10.1002/0471142905.hg0720s76. 
 
 
 
 


Last updated: 03/07/2022 
 
23 
 
APPENDIX A: FORMULATION INSTRUCTIONS FOR GUANFACINE 250 MCG IN LIDOCAINE 
1% PF 6 ML FOR INJECTION (GUANFACINE HYDROCHLORIDE AND LIDOCAINE 1%, 
INJECTION) 
 
Final Product:  
Guanfacine hydrochloride 250 mcg in lidocaine 1% PF 6 mL  
 
 
 
Final Concentration:  41.67 mcg/mL 
 
Supplied: 
 
Guanfacine hydrochloride powder (Procos S.p.A.) 
 
 
 
Storage: 
 
72 hours refrigerated 
 
Dispensing:  
Dispense in a 10 mL syringe with tamper evident leur cap 
 
Supplies:  
 
Guanfacine hydrochloride powder 
 
 
 
Lidocaine 1% PF 30 mL vial 
 
 
 
Weight boat  
 
 
 
5 mL, 10 mL, and 60 mL sterile syringes 
 
 
 
0.22 micron disk filter 
 
MIXING INSTRUCTIONS: 
1. Compounding area is clean, sanitized, and free of components and/or residue of other compounding 
procedures and the compounder is wearing appropriate PPE.  
2. Tare weight boat and print. Weigh 0.03 g of guanfacine hydrochloride powder and print. 
3. Draw up 24 mL Sterile Water (SWFI) and add to weighted guanfacine hydrochloride powder to make aliquot 
(30,000 mcg/24 mL). 
4. Draw up 1 mL of guanfacine aliquot (1250 mcg/mL). 
5. Draw up 29 mL of Lidocaine 1%. 
6. Allow pharmacist(s) to check ingredients (compounding verification) 
7. Pull plunger from a 60 mL syringe and add a tip cap. 
8. Add 29 mL of Lidocaine 1% to barrel. 
9. Add 1 mL of guanfacine aliquot (1250 mcg/mL) to barrel.  
10. Replace plunger and attach a 0.22 micron disc filter and leur to leur adapter to filter 6 mL of solution into the 
final 10 mL syringe. 
11. Add a tamper evident leur cap. 
12. Perform filter integrity test and bubble test on the filter. 
13. Filter integrity test _____PSI    Bubble Test ______ PSI (PASS/FAIL) 
a. The minimum bubble point is 46 psi for this filter unit. Presence of bubbles at less than 46 psi represents 
a filter failure and the compounding process must be aborted. 
b. A successful bubble point test coupled with the satisfactory testing results (sterile per USP<71>) on the 
representative process verification sample performed prior to opening the study serve as criteria for 
release of the dose. 
14. The compounding area is clean and sanitized and free of components and/or residue of this preparation. 
15. Final verification and quality assurance check by: 


Last updated: 03/07/2022 
 
24 
 
 
Pharmacist: ____________________________   Date:___________    Time:___________ 
 
a. Rx Label syringe with a 72 hour expiration refrigerated per USP 797. 
b. The compounded preparation label has been affixed to the final container 
c. High alert sticker has been affixed to final container 
d. “Medication is sterile, Packaging is not” has been affixed to the final container 
e. No particles observed 
f. Final weight and volume of preparation has been verified 
g. Preparation dispensed in an appropriate container 
h. Container is not contaminated by drug 
 
 
FORMULATION INSTRUCTIONS FOR LIDOCAINE 1% PF 6 ML FOR INJECTION (LIDOCAINE 
1%, INJECTION) 
 
Final Product:  
Lidocaine 1% PF 6 mL 
 
 
 
 
Supplied: 
 
n/a 
 
 
 
 
Storage: 
 
72 hours refrigerated 
 
Dispensing:  
Dispense in a 10 mL syringe with tamper evident leur cap 
 
Supplies:  
 
Lidocaine 1% PF 30 mL vial 
 
 
 
10 mL and 30 mL sterile syringes 
 
 
 
0.22 micron disk filter 
 
MIXING INSTRUCTIONS: 
1. Compounding area is clean, sanitized, and free of components and/or residue of other compounding 
procedures and the compounder is wearing appropriate PPE.  
2. Draw up 10 mL of Lidocaine 1%. 
3. Allow pharmacist(s) to check ingredients (compounding verification) 
4. Add Lidocaine 1% to a clean 30 mL syringe. 
5. Attach a 0.22 micron disc filter and leur to leur adapter to filter 6 mL of solution into the final 10 mL syringe. 
6. Add a tamper evident leur cap. 
7. Perform filter integrity test and bubble test on the filter. 
8. Filter integrity test _____PSI    Bubble Test ______ PSI (PASS/FAIL) 
a. The minimum bubble point is 46 psi for this filter unit. Presence of bubbles at less than 46 psi represents 
a filter failure and the compounding process must be aborted. 
b. A successful bubble point test coupled with the satisfactory testing results (sterile per USP<71>) on the 
representative process verification sample performed prior to opening the study serve as criteria for 
release of the dose. 
9. The compounding area is clean and sanitized and free of components and/or residue of this preparation. 
10. Final verification and quality assurance check by: 


Last updated: 03/07/2022 
 
25 
 
 
Pharmacist: ____________________________   Date:___________    Time:___________ 
 
a. Rx Label syringe with a 72 hour expiration refrigerated per USP 797. 
b. The compounded preparation label has been affixed to the final container 
c. High alert sticker has been affixed to final container 
d. “Medication is sterile, Packaging is not” has been affixed to the final container 
e. No particles observed 
f. Final weight and volume of preparation has been verified 
g. Preparation dispensed in an appropriate container 
h. Container is not contaminated by drug 
 
 
 
 
 

ICF_000.pdf: 
   
 
 
 
 
 
 
____________________________________________________________________________________________ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
November 20, 2023 
 
ClinicalTrials.gov PRS – Protocol Registration and Results System 
 
Re: NCT03865940 – Unique Protocol ID: TN – Efficacy of Guanfacine and Lidocaine Combination in 
Trigeminal Nerve Block for Pain Management in Trigeminal Neuropathy  
 
IRB-approved Informed Consent Document  
 


VUMC Institutional Review Board 
Informed Consent Document for Research 
 
Study Title: 
A Randomized, Double-Blind, 2-Way Crossover Trial to Assess the Efficacy of 
Guanfacine and Lidocaine Combination versus Lidocaine Alone in Trigeminal 
Nerve Block for Pain Management in Painful Trigeminal Neuropathy Patients 
Version Date: 06/22/2022 
PI:  David Edwards, M.D. Ph.D.               
 
  
 
 
 
 
1
This box is for 
IRB USE ONLY 
Do not edit or delete 
 
 
Name of participant: __________________________________________ Age: ___________ 
 
The following is given to you to tell you about this research study.  Please read this form with care and 
ask any questions you may have about this study.  Your questions will be answered.  Also, you will be 
given a copy of this consent form.   
 
What is the purpose of this study?  
You are being asked to take part in this research study because you have painful trigeminal neuropathy. 
The purpose of this study is to compare the safety and effectiveness of the drug guanfacine in combination 
with the drug lidocaine to the safety and effectiveness of lidocaine alone in treating the symptoms of 
painful trigeminal neuropathy. Guanfacine is approved by the US Food & Drug Administration (FDA) for 
the treatment of hypertension or attention deficit hyperactivity disorder (ADHD), but guanfacine is 
considered investigational for the purposes of this study. We are seeking to understand whether 
guanfacine will improve your symptoms when given together with lidocaine therapy. After you finish the 
study, we will look at your medical records to determine if there are similarities among the patients who 
improved with guanfacine treatment. This information will help to better identify patients who may 
benefit from guanfacine treatment. Approximately 80 people with painful trigeminal neuropathy will be 
evaluated at Vanderbilt University Medical Center to determine if they are eligible to take part in this 
study.  We expect to enroll 80 subjects with about 34 completing the full study. 
 
You do not have to be in this research study. You may choose not to be in this study and get other 
treatments without changing your healthcare, services, or other rights.  You can stop being in this study 
at any time.  If we learn something new that may affect the risks or benefits of this study, you will be told 
so that you can decide whether or not you still want to be in this study.   Your medical record will contain 
a note saying you are in a research study and may contain some research information about you.  Anyone 
you authorize to receive your medical record will also get this information. 
 
Side effects and risks that you can expect if you take part in this study:  
There are certain risks associated with taking the study drug guanfacine.  Based on the known side effects 
of the study drug, the following risk associated with participation in the study are perceived as low: 
- 
Bradycardia (slow heart rate) 
- 
Hypotension (low blood pressure) 
- 
Dry Mouth 
- 
Sedation 
Date of IRB Approval: 04/27/2023
Date of Expiration: 04/26/2024


VUMC Institutional Review Board 
Informed Consent Document for Research 
 
Study Title: 
A Randomized, Double-Blind, 2-Way Crossover Trial to Assess the Efficacy of 
Guanfacine and Lidocaine Combination versus Lidocaine Alone in Trigeminal 
Nerve Block for Pain Management in Painful Trigeminal Neuropathy Patients 
Version Date: 06/22/2022 
PI:  David Edwards, M.D. Ph.D.               
 
  
 
 
 
 
2
This box is for 
IRB USE ONLY 
Do not edit or delete 
 
- 
Dizziness 
- 
Headache 
- 
Bruising, redness, itching, or swelling at the site of injection 
- 
Intravenous injection resulting in seizure or stroke 
- 
Bleeding 
- 
Increased pain 
 
Pregnancy 
Guanfacine is classified as FDA pregnancy category B. This means that animal studies have failed to 
demonstrate a risk to the fetus and there are no adequate and well-controlled studies in pregnant women. 
If you are a female who could get pregnant, we will do a urine pregnancy test to make sure you are not 
pregnant. If you are pregnant, you will not be able to be in the study. 
  
Risks that are not known: 
Because this treatment is investigational, meaning non-FDA approved, there may be risks that we do not 
know about at this time. There is no human or animal data regarding the safety of guanfacine for nerve 
block injection in combination with lidocaine. 
 
Good effects that might result from this study:  
a.) The benefits to science and humankind that might result from this study: We may learn about using 
guanfacine as a new adjunct treatment for painful trigeminal neuropathy. 
 
 
b.) The benefits you might get from being in this study: You may experience an improvement in your pain.  
You may also not benefit from participating in this study. 
 
Procedures to be followed: 
If you agree to be in this study, we will ask you to come to the Vanderbilt Pain Clinic for an initial screening 
visit and two procedure visits. Total expected duration of your participation is 5-8 weeks. At the screening 
visit, we will ask you about your medical history to be sure you are eligible to be in the study. You will 
report your pain intensity and quality of life on standardized surveys. If your pain intensity does not score 
at or above a pre-determined threshold, we cannot enroll you in the study.  
 
Following the screening visit, there will be two procedure visits during the study. During the first 
procedural visit you will receive with an injection of lidocaine alone or an injection of lidocaine plus the 
investigational drug guanfacine. You will not know which injection you receive, and no one on the study 
Date of IRB Approval: 04/27/2023
Date of Expiration: 04/26/2024


VUMC Institutional Review Board 
Informed Consent Document for Research 
 
Study Title: 
A Randomized, Double-Blind, 2-Way Crossover Trial to Assess the Efficacy of 
Guanfacine and Lidocaine Combination versus Lidocaine Alone in Trigeminal 
Nerve Block for Pain Management in Painful Trigeminal Neuropathy Patients 
Version Date: 06/22/2022 
PI:  David Edwards, M.D. Ph.D.               
 
  
 
 
 
 
3
This box is for 
IRB USE ONLY 
Do not edit or delete 
 
team will know which injection you receive. You will be randomized 1:1 like the flip of a coin. After the 
injection procedure, you will report the intensity of your pain on a scale of 1-10 every 30 minutes for 8 
hours and then daily for 14 days. You will have the option to record pain scores in a paper diary or using 
an easy text messaging system.  If your pain is rated at a pre-determined threshold at the end of those 14 
days, you will attend study visit 3 to receive your second injection. This injection will be the opposite 
treatment from what you received at study visit 2. Following the second injection you will again rate your 
pain intensity every 30 minutes for 8 hours and then daily for 14 days.  
 
If your pain is below the pre-determined threshold at the end of the first 14 day period following study 
visit 2, study staff will periodically reach out to you to evaluate if your pain exceeds the pre-determined 
threshold. If your pain exceeds the pre-determined threshold,  you may then be scheduled for study visit 
3 and the study will proceed as described above. However, you will be discontinued from the study and 
will not attend study visit 3 and receive the second injection if your pain does not meet the predetermined 
threshold. 
 
Your reports of how your pain changes in response to the investigational drug will be used to develop 
knowledge that may improve the treatments for painful trigeminal neuropathy. To protect your privacy, 
we will not release your name or any other information that might identify you. 
 
Screening Visit 
This visit will take approximately 1 hour. You will come into the Pain Clinic where we will ask you some 
questions about your medical history, conduct a physical exam, take your blood pressure, weigh you, and 
get an initial pain intensity rating. If you are a woman who could become pregnant, we will ask you if you 
believe you could be pregnant. If it is possible that you are pregnant, you will be ineligible for this study. 
We will ask women who could become pregnant to commit to using 2 forms of birth control throughout 
the duration of the study. We will review recent MRI or CT imaging to ensure safety of the nerve block 
injection. If no recent imaging exists, this will be ordered as part of standard care prior to nerve block. 
 
Patients that meet final eligibility criteria for this study will move forward to the procedural visits. If you 
are eligible for the study, a study coordinator will work with you during your visit to schedule procedure 
visit 1, which will take place approximately one week after the screening visit. 
 
Procedure Visits 1 and 2 
At procedure visit 1, you will be asked to report your pain intensity and you will receive a nerve block 
injection of either the investigational drug (guanfacine + lidocaine) or the active control (lidocaine only). 
Date of IRB Approval: 04/27/2023
Date of Expiration: 04/26/2024


VUMC Institutional Review Board 
Informed Consent Document for Research 
 
Study Title: 
A Randomized, Double-Blind, 2-Way Crossover Trial to Assess the Efficacy of 
Guanfacine and Lidocaine Combination versus Lidocaine Alone in Trigeminal 
Nerve Block for Pain Management in Painful Trigeminal Neuropathy Patients 
Version Date: 06/22/2022 
PI:  David Edwards, M.D. Ph.D.               
 
  
 
 
 
 
4
This box is for 
IRB USE ONLY 
Do not edit or delete 
 
At procedure visit 2, you will report your pain intensity and receive the opposite injection that you 
received at study visit 1. If you are a woman who could become pregnant, you will undergo a urine 
pregnancy test before each injection. You will be free to stop participating in the study at any time. Any 
information provided up until the time you withdraw may be used in the study. You will be monitored for 
pain intensity at 30-minute time intervals for the first 8 hours after block and then monitored once daily 
at the same timepoint for 14 days using a text message generated using REDCap (or if needed a paper 
diary). 
 
2-3 weeks after your first procedure visit you will return to the clinic to receive the other treatment 
injection at your second procedure visit. Once again, you will be monitored for pain intensity at 30-minute 
time intervals for the first 8 hours after block and then monitored once daily at the same timepoint for 14 
days. 
 
Payments for your time spent taking part in this study or expenses: 
You will be paid for your time for being in this research study ($50 per procedure visit). You will need to 
provide your social security number (SSN) in order for us to pay you. You may choose to participate 
without being paid if you do not wish to provide your SSN for this purpose. You will also need to provide 
your address so that a gift card will be mailed to you. Your SSN is obtained for payment purposes only and 
it will not be retained for research purposes. It may take up to 4-6 weeks to receive your gift card following 
completion or withdrawal from the study.  
 
Costs to you if you take part in this study: 
There is no extra cost to you for taking part in this study. 
 
Payment in case you are injured because of this research study: 
If it is determined by Vanderbilt and the Investigator that an injury occurred as a direct result of the tests 
or treatments that are done for research, then you and/or your insurance will not have to pay for the cost 
of immediate medical care provided at Vanderbilt to treat the injury.  
 
There are no plans for Vanderbilt to pay for any injury caused by the usual care you would normally receive 
for treating your illness or the costs of any additional care. There are no plans for Vanderbilt to give you 
money for the injury.  
 
 
 
Date of IRB Approval: 04/27/2023
Date of Expiration: 04/26/2024


VUMC Institutional Review Board 
Informed Consent Document for Research 
 
Study Title: 
A Randomized, Double-Blind, 2-Way Crossover Trial to Assess the Efficacy of 
Guanfacine and Lidocaine Combination versus Lidocaine Alone in Trigeminal 
Nerve Block for Pain Management in Painful Trigeminal Neuropathy Patients 
Version Date: 06/22/2022 
PI:  David Edwards, M.D. Ph.D.               
 
  
 
 
 
 
5
This box is for 
IRB USE ONLY 
Do not edit or delete 
 
Who to call for any questions or in case you are injured: 
If you should have any questions about this research study or if you feel you have been hurt by being a 
part of this study, please feel free to contact Patty Hendricks, RN (Study Coordinator) at 615-936-2831 or 
David Edwards, MD/PhD (Principal Investigator) at 615-343-9419. 
 
For additional information about giving consent or your rights as a person in this study, to discuss 
problems, concerns, and questions, or to offer input, please feel free to call the VUMC Institutional Review 
Board Office at (615) 322-2918 or toll free at (866) 224-8273. 
 
Reasons why the study doctor may take you out of this study:  
You will be withdrawn from the study if the study doctors decide it is best for you. If the study doctors 
withdraw you from the study, you will be told the reason. 
 
What will happen if you decide to stop being in this study? 
If you decide to stop being part of the study, you should tell your study doctor.  Deciding to not be part of 
the study will not change your regular medical care in any way. 
 
Clinical Trials Registry:  
A description of this clinical trial will be available on www.clinicaltrials.gov, as required by U.S. Law.  This 
website will not include information that can identify you.  At most, the website will include a summary 
of the results.  You can search this website at any time. 
 
Confidentiality:   
All efforts, within reason, will be made to keep your personal information in your research record 
confidential but total confidentiality cannot be guaranteed. The study results will be kept in your research 
record for at least six years after the study is over for as long as we need the information for the study. All 
the information on paper will be kept locked in a secure location. Any information kept in a computer will 
be through REDCap or the Vanderbilt Pain Clinic, which has many safeguards. Only members of Dr. 
Edward’s research team will be able to see any of the information that would identify you. Any research 
data entered into your medical record will be kept as long as it is needed. 
 
Vanderbilt may share your information, without identifiers, to others or use it for other research projects 
not listed in this form. Vanderbilt, Dr. Edwards and his staff will comply with any and all laws regarding 
the privacy of such information.  There are no plans to pay you for the use or transfer of this de-identified 
information. 
Date of IRB Approval: 04/27/2023
Date of Expiration: 04/26/2024


VUMC Institutional Review Board 
Informed Consent Document for Research 
 
Study Title: 
A Randomized, Double-Blind, 2-Way Crossover Trial to Assess the Efficacy of 
Guanfacine and Lidocaine Combination versus Lidocaine Alone in Trigeminal 
Nerve Block for Pain Management in Painful Trigeminal Neuropathy Patients 
Version Date: 06/22/2022 
PI:  David Edwards, M.D. Ph.D.               
 
  
 
 
 
 
6
This box is for 
IRB USE ONLY 
Do not edit or delete 
 
 
This study may have some support from the National Institutes of Health (NIH). If so, your study 
information is protected by a Certificate of Confidentiality.  This Certificate allows us, in some cases, to 
refuse to give out your information even if requested using legal means.  
  
It does not protect information that we have to report by law, such as child abuse or some infectious 
diseases.  The Certificate does not prevent us from disclosing your information if we learn of possible 
harm to yourself or others, or if you need medical help.  
  
Disclosures that you consent to in this document are not protected. This includes putting research data in 
the medical record or sharing research data for this study or future research. Disclosures that you make 
yourself are also not protected. 
 
Privacy: 
Any samples and information about you may be made available to others to use for research.  To protect 
your privacy, we will not release your name.  You will not receive any benefit as a result of the tests done 
on your samples.  These tests may help us or other researchers learn more about the causes, risks, 
treatments, or how to prevent this and other health problems.  
 
Study Results: 
Study results will be published in medical journals and submitted to www.clinicaltrials.gov as described 
above.  Published study results will not include information that can identify you; at most, publications 
will include a summary of the results.   
 
Authorization to Use/Disclose Protected Health Information 
What information is being collected, used, or shared? 
To do this research, we will need to collect, use, and share your private health information.  By signing 
this document, you agree that your health care providers (including both Vanderbilt University Medical 
Center and others) may release your private health information to us, and that we may use any and all of 
your information that the study team believes it needs to conduct the study.  Your private information 
may include things learned from the procedures described in this consent form, as well as information 
from your medical record (which may include information such as HIV status, drug, alcohol or STD 
treatment, genetic test results, or mental health treatment).    
  
 
Date of IRB Approval: 04/27/2023
Date of Expiration: 04/26/2024


VUMC Institutional Review Board 
Informed Consent Document for Research 
 
Study Title: 
A Randomized, Double-Blind, 2-Way Crossover Trial to Assess the Efficacy of 
Guanfacine and Lidocaine Combination versus Lidocaine Alone in Trigeminal 
Nerve Block for Pain Management in Painful Trigeminal Neuropathy Patients 
Version Date: 06/22/2022 
PI:  David Edwards, M.D. Ph.D.               
 
  
 
 
 
 
7
This box is for 
IRB USE ONLY 
Do not edit or delete 
 
 
Who will see, use or share the information? 
The people who may request, receive or use your private health information include the researchers and 
their staff.  Additionally, we may share your information with other people at Vanderbilt, for example if 
needed for your clinical care or study oversight.  By signing this form, you give permission to the research 
team to share your information with others outside of Vanderbilt University Medical Center.  This may 
include the sponsor of the study and its agents or contractors, outside providers, study safety monitors, 
government agencies, other sites in the study, data managers and other agents and contractors used by 
the study team.   We try to make sure that everyone who sees your information keeps it confidential, but 
we cannot guarantee that your information will not be shared with others.  If your information is disclosed 
by your health care providers or the research team to others, federal and state confidentiality laws may 
no longer protect it.  
  
Do you have to sign this Authorization? 
You do not have to sign this Authorization, but if you do not, you may not join the study. 
  
How long will your information be used or shared? 
Your Authorization for the collection, use, and sharing of your information does not expire.  Additionally, 
you agree that your information may be used for similar or related future research studies. 
  
What if you change your mind? 
You may change your mind and cancel this Authorization at any time.  If you cancel, you must contact the 
Principal Investigator in writing to let them know by using the contact information provided in this consent 
form.  Your cancellation will not affect information already collected in the study, or information that has 
already been shared with others before you cancelled your authorization. 
 
 
 
 
 
 
 
 
 
 
Date of IRB Approval: 04/27/2023
Date of Expiration: 04/26/2024


VUMC Institutional Review Board 
Informed Consent Document for Research 
 
Study Title: 
A Randomized, Double-Blind, 2-Way Crossover Trial to Assess the Efficacy of 
Guanfacine and Lidocaine Combination versus Lidocaine Alone in Trigeminal 
Nerve Block for Pain Management in Painful Trigeminal Neuropathy Patients 
Version Date: 06/22/2022 
PI:  David Edwards, M.D. Ph.D.               
 
  
 
 
 
 
8
This box is for 
IRB USE ONLY 
Do not edit or delete 
 
If you decide not to take part in this research study, it will not affect your treatment, payment or 
enrollment in any health plans or affect your ability to get benefits. You will get a copy of this form after 
it is signed.  
 
 
 
 
STATEMENT BY PERSON AGREEING TO BE IN THIS STUDY 
 
I have read this consent form and the research study has been explained to me verbally.  All my 
questions have been answered, and I freely and voluntarily choose to take part in this study.    
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Date 
 
 
 
 
Signature of patient/volunteer  
 
 
 
 
 
Consent obtained by:  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Date 
 
 
 
 
Signature 
 
 
 
 
 
 
 
 
 
 
 
 
 
Printed Name and Title 
 
Time: ______________  
 
 
Date of IRB Approval: 04/27/2023
Date of Expiration: 04/26/2024