A Prospective Controlled Treatment Trial for Post-Traumatic Headaches
Phase: PHASE3
Conditions: Post-Traumatic Headaches
Sponsor: Boston Children's Hospital

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Date: July 14, 2022 
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Protocol Title: A Prospective Controlled Treatment Trial for Post-Traumatic 
Headaches 
NCT#: 03007420 
Principal Investigator: Pradeep Dinakar, MD 
A.  SPECIFIC AIMS AND HYPOTHESIS 
1. To compare the efficacy of Occipital Nerve Blocks (ONB) vs. Cervical Medial Branch 
Blocks (CMBB) in patients presenting with post-traumatic headache (PTH) who were non-
responsive to previous interventional management. 
• 
To examine differences in Numeric Rating Scale (NRS) pain measurements (> 
50% or < 50% pain reduction) 
• 
To examine differences in Migraine Disability Assessment (MIDAS) and 
Pediatric Migraine Disability Assessment (PedMIDAS) scores 
• 
To describe differences in functional outcomes using the Functional Disability 
Inventory (FDI) and the Pain Disability Index (PDI). 
• 
To study differences in Quality of Life (QL) and Pediatric Quality of Life 
(PedsQL) scores 
Hypothesis: Treatment with CMBB with steroids and lidocaine will be associated with a greater 
improvement in pain scores, functional and QL scores than the ONB.   
2. To describe the baseline socio-demographic characteristics of individuals with PTH 
and chronic axial neck pain. 
• 
To study gender, BMI, age, school and work absences and disrupted sleep  
• 
To study psychological (anxiety, depression) and pain related comorbidities 
(whole body pain, gastrointestinal problems, small fiber neuropathy)  
• 
To study correlation to nature of injury (concussion vs. head injury and severity 
of injury based on 1997 AAN guidelines)  
• 
To study previous treatment methods and interventions 

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Hypothesis: Of the participants with PTH, the majority will exhibit school or work absences and 
disrupted sleep. The majority of participants will also have higher scores of anxiety and depression, 
more pain related comorbidities, history of prior injury, and previous treatment from other 
providers.   
3. To describe and understand how clinical features, physical exam characteristics, and 
radiologic findings among patients with PTH and axial neck pain associate with 
treatment response for each of the treatment options.  
• 
To assess physical exam characteristics (axial neck pain which is extension 
related, myofascial spasms and occipital neuralgia) 
• 
To characterize the diagnosis given by the clinicians in their notes 
• 
To characterize the presence of radiologic or predictive clinical findings such 
as facet arthropathy, disc changes, spondylolysis, or spondylolisthesis  
Hypothesis: Treatment response (improvement in pain) will be associated with features on the 
physical exam (neck pain with extension, headaches associated with cervicogenic causes) and with 
presumed anatomic diagnosis (facet arthropathy, spondyloysis, spondylolisthesis, axial and 
discogenic pain). 
4. To study the effects of socio-demographic, clinical, and psychosocial predictor 
variables on CMBB and ONB treatment outcomes.   
Hypothesis: The likelihood of improvement with CMBB or ONB is associated with a combination 
of socio-demographic, clinical/anatomic, and psychosocial variables. Improved responses 
following treatment with ONB and CMBB will be associated with a shorter duration of pain prior 
to intervention, normal weight, younger age and lack psychological comorbidities. 
5. To study the safety of the ONB and CMBB treatment.  
• 
To study fluoroscopy time and amount of radiation exposure 
• 
To study sedation method if any including the use of propofol, benzodiazepine 
or fentanyl vs. awake procedure 
• 
To study anesthetic complications  

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Hypothesis: The time of fluoroscopy and radiation exposure will be low, and anesthetic 
complications or side effects will be minimal.   
 
 
B. Background and Significance 
PTH is the most common physical symptom following concussion1, 2 with up to 36% of athletes 
reporting headaches throughout the first year after concussion. PTH is defined as a secondary 
headache disorder through ICDH-3 criteria2. There is an estimated 3.8 million sports related 
concussions in the US each year, and concussion has become an important global health issue in 
recent years3. PTH pathophysiology is predominantly migrainous and cervicogenic in nature4. 
Neurogenic inflammation after head injury can lead to activation of meningeal nociceptors and the 
trigeminovascular system leading to development of post-traumatic migraine. This can be 
secondary to direct injury of the trigeminal afferent nerves or to leptomeningeal or cerebrovascular 
structures innervated by trigeminal nerves. Activated glial cells, with increased production of pro-
inflammatory substances have been implicated in the development and persistence of pain. The 
neuronal-glial signaling is suspected to play a role in sensitizing afferent trigeminal nociceptors. 
Prolonged inflammation and chronic hyper excitability are thought to predispose to a pathological 
pain state5.  
In addition, a common etiology of headache and neck pain in football related concussions is 
whiplash associated disorder (WAD)6, secondary to acceleration-deceleration injuries. Pain may 
be generated by inflammation of the high cervical facet joints7, traumatic neuralgias and 
myofascial injury8. Occipital headaches result from activation of the sensory branches of C2 and 
C3 peripherally, causing occipital neuralgia, with cervical facet inflammation and myofascial 
spasms resulting in cervicogenic headaches. The reported convergence of sensory C2 and the 
nucleus caudalis of the trigeminal nerve may result in exacerbation of post-traumatic migraines9,10, 
and therefore treatment of cervicogenic headache etiologies could also improve post-traumatic 
migraines. The mechanism of overlap between the trigeminal nerve and the cervical nerves is 
known as convergence, whereby trigeminal nerve activation produces symptoms in the trigeminal 
and cervical territories and cervical activation produces symptoms in the cervical and trigeminal 
territory11. In addition, multiple lifetime concussions in older and retired football players with 

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subsequent chronic cervical facet inflammation increase the risk of degenerative cervical arthritis 
and, therefore, the risk of cervicogenic headaches, which due to convergence also increases the 
risk of post-traumatic migraines11.  
Headache and neck pain following concussion are potentially treatable and resolve over time. 
Nerve blockade may enhance the recovery of appropriate neural circuits involved in the 
pathophysiology of chronic headache. Currently, no evidence-based guidelines exist for treatment 
of PTH. Adoption of "brain rest" for 1-2 weeks, followed by gradual return to activity and avoiding 
“second-impact syndrome“ are current practice. The use of medications controlling neuropathic 
pain is of partial benefit for some patients and requires several weeks to evaluate, and as many 
take 4-6 weeks to show effect.10 Adverse effects like sedation, mood changes, cardiac side effects 
of pharmacologic agents are often not compatible with the demands of athletics. For those patients 
where sports performance is paramount, they may therefore not be able to tolerate typical 
medications. Incidence of chronic post-concussive headaches (> 3 months) at 1 year is 8.4% - 35% 
and at 4 years is up to 25%.11 Therefore, patients can have significant disability from their post-
traumatic headaches for many years after their injury.  Without appropriate treatment, these 
headaches can remain as chronic headaches. Over-the-counter and other symptomatic medication 
overuse can exacerbate and prolong PTH significantly, secondary to rebound headaches2. 
Successful treatment is essential since PTH limits return to sports as well as more general activities 
of living, such as work and school.  Most interventions currently in use partially help and take 
several weeks to months for noticeable benefit. Additionally, a multicenter, double-blind, placebo-
controlled trial recently published in The New England Journal of Medicine showed no significant 
differences among amitriptyline, topiramate and placebo in reducing headache days or related 
disability after a 24-week period, and showed an increase in side effects (Powers et al, NEJM 
2016). PTH interventions, including ONB and CMBB are used in the treatment of primary 
headache disorders and neck pain from cervical arthritis and may provide more improved, faster 
and more sustained pain relief in many patients12. In addition, given that most of the action of the 
nerve blocks is local, there are significantly fewer side effects than in more typical headache 
medications. Injections that use corticosteroids may be beneficial in post-traumatic headache by 
reducing inflammation and therefore mechanical allodynia13. Injection of corticosteroids in the 
cervical facet joint area has shown up to 13 months of pain relief 12. This prolonged effect may be 

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secondary to central pain modulation13. Ultimately, nerve blocks may be a more effective and 
efficient post-traumatic headache given the onset of effect and the minimal side effects.  
To date, there have been no prospective studies of procedural treatments for medically refractory 
PTH and none in the adolescent and young adult population in whom football injuries are common. 
Despite the frequent clinical practice of using ONB and CMBB for occipital neuralgia, cervical 
arthritis and cervicogenic headaches, there has been no adequate scientific investigation into the 
use of these interventions for PTH. Given that PTH is typically felt to be secondary to 
inflammatory reaction to trauma, the use of injection of corticosteroids may be more effective in 
PTH than in typical headache disorders. There is also no adequate comparison of these 
interventions to medications.   
C.  PRELIMINARY STUDIES 
There are no preliminary studies comparing the effect of interventions and medications on PTH to 
date. 
D.  DESIGN AND METHODS 
1.  
Study Design  
We propose a randomized, controlled clinical trial and prospective follow up to evaluate the effect 
of invasive procedures in the management of PTH. Adolescents and young adults will be recruited 
from Boston Children’s Hospital, Beth Israel Deaconess Medical Center, and Mass General 
Brigham Pain clinics, Concussion clinics and Headache clinics. Patients will be recruited 
beginning July 2017.   
We propose to study the effect of CMBB versus ONB treatment with lidocaine and steroids. Patient 
demographics (e.g. age, sex, ethnicity, and race), disease characteristics (e.g. symptoms, duration 
of the disease, medications taken, etc.), and description of the intervention will be collected. As 
part of the standard of clinical care at the study sites, patients will complete the intake Standard 
Pain Questionnaire at baseline. During the first two months of the study, patients will be contacted 
by our research team via email on a weekly basis requesting them to complete a study 
questionnaires. After the initial 2 months on the study, we will continue to contact patients every 
2 weeks over the next 10-months.  Patients will remain in the study up to 12 months after 
enrollment.  
2.  Patient Selection and Inclusion/Exclusion Criteria     

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Patients who meet the criteria below will be recruited from Boston Children’s Hospital, Beth Israel 
Deaconess Medical Center, and Mass General Brigham Pain clinics, Concussion clinics and 
Headache clinics.  
Inclusion Criteria:  
• 
Age 14 – 45 years. 
• 
History of post-traumatic headache or neck pain following a concussion or head injury 
within the last 2 years. 
• 
Self-reported lack of meaningful benefit with at least one previous treatment 
trial. Previous treatment could include a migraine prophylactic medication, a 
neuropathic pain medication, a physical intervention, or a cognitive-behavioral 
intervention. 
Exclusion Criteria: Subjects will be excluded in the following circumstances: 
• 
Significant underlying psychological concerns, as determined by study psychologist up on 
review of standardized assessment 
• 
Lack of parental consent and child assent (if patient age <18 years) or lack of consent (if 
patient age >18 years). Unable to complete the questionnaire, based on parental or patient 
estimation of cognitive or language limitations 
3.  Description of Study Treatments or Exposures/Predictors 
Patients enrolled in the study will be randomized to receive either an ONB (Figure 2, additional 
procedure details provided below) with dexamethasone 2mg each site with 3ml 1% lidocaine, for 
a total of two sites or a CMBB (Figure 3a & 3b, additional procedure details provided below) with 
dexamethasone 1.5mg each site with 2 ml 1% lidocaine, for a total of three sites on each side. The 
assignment of the procedure will be randomized however neither the patients nor the investigator 
will be blinded to the procedure. If patients exhibit a >50% pain reduction on receiving the block 
evaluated after four weeks, then they may continue to receive blocks as needed, but not more than 
one every three months. If patients exhibit < 50% pain reduction, the patient will be treated as per 
the clinician’s judgment with the possibility of a cross over to the other treatment option in the 
protocol.   
All patients will be followed for 12 months after enrollment and after the crossover of treatments 
they will continue to be treated and followed per clinical standard of care. 

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As part of this study, patients will need to complete 8 follow-up visits, of which the first and second 
will be in-person clinical visits and the other follow-ups could either be conducted in-person at the 
clinic or via teleconference - video:  
a) 
Visit 1: in-person clinic visit 
• At the first visit to the clinic, the physician or nurse will verify the patient’s name and 
date of birth, and will collect information about pain, current and past medicines, and 
general health. The physician will perform a physical examination and measure heart 
rate, blood pressure and respiratory rate, and conduct a neurological exam.  
• Baseline questionnaires will be taken, including Pain (NRS), Concussion Symptom 
Score, MIDAS/PedMIDAS, Anxiety, Depression, FDI, and QL. 
At the end of the visit, all enrolled patients will be randomized to one of the two minimally invasive 
procedures, the ONB or the CMBB. Information from the patient’s most recent clinical visit note 
(retrieved from the patient’s medical record) may be used to obtain Visit 1 data. 
b) Visit 2:  Cervical and medial branch block procedures 
The procedure will be performed at Boston Children’s Hospital or Beth Israel Deaconess Medical 
Center or Mass General Brigham Operation Room. Patients may receive sedation as per clinical 
need, and procedures will be performed in a standardized manner. Neither the patient nor the 
investigator will be blinded to the type of procedure.  
Patients will not be universally sedated however a particular subset of patients may receive 
sedation. Pediatric patients and some adults with extreme anxiety to procedures will receive mild 
IV sedation with fentanyl, midazolam and occasionally propofol. This is not general anesthesia 
but is Monitored Anesthesia Care (MAC). Patients will be awake enough to report any symptoms 
or discomfort. Anesthesia will be administered either in an Operating Room or Day Surgery Unit 
setting of the study sites and not in an outpatient setting. A separate anesthesia team consisting of 
an anesthesiologist and nurse anesthetist (CRNA) will be responsible for administration of 
anesthesia and airway maintenance. Vital signs will be monitored every 5 minutes and anesthesia 
adjusted based on patient discomfort.  
Details on doses of dexamethasone and lidocaine to be used: 
Dexamethasone doses: 

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Occipital nerve block: 2 mg / block  
Cervical facet injections/medial branch block: 1.5 mg / facet joint 
Lidocaine doses: 
Occipital nerve block: 3 ml of 1% lidocaine / block 
Cervical facet injections/medial branch block: 2 ml of 1% lidocaine / facet joint 
DESCRIPTION OF OCCIPITAL NERVE BLOCK:  
The patient will be in the seated position. The back of the head (occipital area) will be prepped 
with alcohol pads.  Following this, the left or right greater occipital nerve will be accessed at the 
midpoint of the occipital protuberance and the mastoid process using a 25-gauge 1-1/2 inch needle. 
1% lidocaine will be used for skin and subcutaneous analgesia. Following this, area of the left 
greater occipital nerve will be accessed and the injection fanned. A mixture of 2 mg of 
dexamethasone and 3 ml of 1% lidocaine will be injected into this area. Following this, the 
contralateral side will be addressed in a similar fashion (if patient needs bilateral injection). A total 
of 4 mg of dexamethasone and 6 mL of 1% lidocaine will be injected. The patient will be observed 
in recovery for complications of bleeding, worsening of symptoms, or paresthesias.  
DESCRIPTION OF CERVICAL FACET / MEDIAL BRANCH BLOCK: 
The patient will be placed in the prone position in the procedure room on a Steris table with 
fluoroscopy. The back of the neck will be prepped and draped in the usual sterile fashion with 
ChloraPrep. Under fluoroscopy guidance the high cervical facets will be visualized in AP, oblique 
and lateral views. Using a 22-gauge, 2-1/2-inch spinal needle, the left C 4-5 facet joint/medial 
branch area will accessed under fluoroscopy. 1% lidocaine will be used for the skin and 
subcutaneous analgesia. Contrast omnipaque 300 mg/ ml, 0.5 ml will be used to confirm the needle 
position. Similar procedures will be repeated at C2-3 and C 3-4 levels. Similar procedures will be 
done on the corresponding levels on the contralateral side.  Dexamethasone 1.5 mg with 2 mL of 
1% lidocaine will be injected at each of these levels. A maximum of 9 mg of dexamethasone will 
be used. The patient will be observed in recovery for complications of bleeding, worsening of 
symptoms or paresthesias.  
After the procedure is completed, all patients will recover in the Post Anesthesia Care Unit 
(PACU). Patients will be examined and they will be required to complete questionnaires. Patients 
will be discharged from the hospital per hospital guidelines and standard of clinical practice. 

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c) Visit 3 to 8:  in-person visit or tele-conference 
At 1, 2, 3, 6, 9, and 12 months after enrollment, patients will be evaluated to determine how well 
they did after the procedures. This would include the same steps from previous appointments. If 
the study treatment has been helpful, the physician might decide to continue the treatment with the 
procedures as needed. Clinical criteria and patient – physician agreement would be used to 
determine next steps in the patient’s treatment plan.  
d) E-mail questionnaires: 
During the first two months of the study, patients will be contacted by our research team via email 
on a weekly basis requesting them to complete a short questionnaire that includes questions about 
their pain scores (NRS), MIDAS/ PedMIDAS, QL, FDI, Anxiety, Depression, and Concussion 
Symptoms Score. After the initial 2 months on the study, we will continue to contact patients every 
2 weeks over the next 10-months (follow-ups over a total of 12 months). See Table 1 below for 
REDCap survey schedule.  
Table 1: Schedule of REDCap surveys 
Follow-Up 
Questionnaire 
Week 0 
Migraine disability  
Pain Assessment 
Concussion Score 
General functionality 
Quality of Life 
Anxiety 
Depression 
Week 1 
Pain Assessment 
Concussion Score 
General Functionality 
Side Effects Related to Invasive Treatment 
Week 2 
Pain Assessment 
Concussion Score 
General Functionality 
Side Effects Related to Invasive Treatment 
Week 3 
Pain Assessment 
Concussion Score 
General Functionality 
Side Effects Related to Invasive Treatment 
Improvement Evaluation 1m 
Pain Assessment 
Concussion Score 
General Functionality 

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Side Effects Related to Invasive Treatment 
Improvement 
Additional Procedures 
Week 5 
Pain Assessment 
Concussion Score 
General Functionality 
Side Effects Related to Invasive Treatment 
Week 6 
Pain Assessment 
Concussion Score 
General Functionality 
Side Effects Related to Invasive Treatment 
Week 7 
Pain Assessment 
Concussion Score 
General Functionality 
Side Effects Related to Invasive Treatment 
Improvement Evaluation 2m 
Pain Assessment 
Concussion Score 
General Functionality 
Side Effects Related to Invasive Treatment 
Quality of Life 
Anxiety 
Depression 
Improvement 
Additional Procedures 
Week 10 
Pain Assessment 
Concussion Score 
General Functionality 
Side Effects Related to Invasive Treatment 
Improvement Evaluation 3m 
Migraine disability  
Pain Assessment 
Concussion Score 
General Functionality 
Side Effects Related to Invasive Treatment 
Quality of Life 
Anxiety 
Depression 
Improvement 
Additional Procedures 
Week 14 
Pain Assessment 
Concussion Score 
General Functionality 
Side Effects Related to Invasive Treatment 
Week 16 
Pain Assessment 
Concussion Score 
General Functionality 

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Side Effects Related to Invasive Treatment 
Week 18 
Pain Assessment 
Concussion Score 
General Functionality 
Side Effects Related to Invasive Treatment 
Week 20 
Pain Assessment 
Concussion Score 
General Functionality 
Side Effects Related to Invasive Treatment 
Week 22 
Pain Assessment 
Concussion Score 
General Functionality 
Side Effects Related to Invasive Treatment 
Improvement Evaluation 6m 
Migraine disability  
Pain Assessment 
Concussion Score 
General Functionality 
Side Effects Related to Invasive Treatment 
Quality of Life 
Anxiety 
Depression 
Improvement 
Additional Procedures 
Week 26 
Pain Assessment 
Concussion Score 
General Functionality 
Side Effects Related to Invasive Treatment 
Week 28  
Pain Assessment 
Concussion Score 
General Functionality 
Side Effects Related to Invasive Treatment 
Week 30 
Pain Assessment 
Concussion Score 
General Functionality 
Side Effects Related to Invasive Treatment 
Week 32 
Pain Assessment 
Concussion Score 
General Functionality 
Side Effects Related to Invasive Treatment 
Week 34 
Pain Assessment 
Concussion Score 
General Functionality 
Side Effects Related to Invasive Treatment 
Improvement Evaluation 9m 
Migraine disability  
Pain Assessment 

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Concussion Score 
General Functionality 
Side Effects Related to Invasive Treatment 
Quality of Life 
Anxiety 
Depression 
Improvement 
Additional Procedures 
Week 38 
Pain Assessment 
Concussion Score 
General Functionality 
Side Effects Related to Invasive Treatment 
Week 40 
Pain Assessment 
Concussion Score 
General Functionality 
Side Effects Related to Invasive Treatment 
Week 42 
Pain Assessment 
Concussion Score 
General Functionality 
Side Effects Related to Invasive Treatment 
Week 44 
Pain Assessment 
Concussion Score 
General Functionality 
Side Effects Related to Invasive Treatment 
Week 46 
Pain Assessment 
Concussion Score 
General Functionality 
Side Effects Related to Invasive Treatment 
Improvement Evaluation 12m 
Migraine disability  
Pain Assessment 
Concussion Score 
General Functionality 
Side Effects Related to Invasive Treatment 
Quality of Life 
Anxiety 
Depression 
Improvement 
Additional Procedures 
 

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Figure 1: Study design for a prospective controlled trial in posttraumatic headaches  

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Figure 2: Occipital nerve blocks (ONB). (Adapted from Waldman SD. Atlas of interventional Pain 
Management. 2nd ed. Philadelphia: Elsevier; 2004.) The ONB site of injection is determined at 
the midpoint of the line joining the mastoid process and external occipital protuberance.  
 

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Figure 3a: Cervical medial branch block (CMBB) posterior approach targeting the medial branch 
of the dorsal ramus of the spinal nerves 
 
Figure 3b: Cervical medial branch block (CMBB) posterior approach fluoroscopy view 
 
E. Definition of Primary and Secondary Outcomes / Endpoints: 
Primary Outcome Measures   
The overall goal of this study is to examine the change in PTH and / or axial neck pain in groups 
of patients receiving minimally invasive nerve block interventions (ONB with lidocaine and 
steroids vs. CMBB with lidocaine and steroids). The primary outcome is defined as change in pain 

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intensity scores (NRS), which will be collected at baseline, weekly for two months, and then bi-
weekly throughout rest of the study. 
Pain scales: The numerical rating scale (NRS) will be utilized in this study. Patients will rate their 
pain score on a scale of 0 to 10 with 0 being no pain and 10 being the worst pain imaginable. 
Secondary Outcome Measure 
The secondary outcome measures include data about associated pain and psychological 
comorbidities, and concomitant effects of intervention.   
• 
Headache frequency and severity: The MIDAS14 and PedMIDAS15 are brief 
questionnaires, which are self-administered to quantify headache-related disability. The 
MIDAS score has been shown to have moderately high test-retest reliability in headache 
sufferers and is correlated with clinical judgment regarding the need for medical care. 
• 
Functional Disability: The Functional Disability Inventory (FDI) 16, 17 is a valid and reliable 
measure consisting of 15 items concerning perceptions of physical and psychosocial 
functioning. Total scores range from 0 to 60 with higher scores indicating greater disability.  
The Pain Disability Index (PDI) is a simple and rapid instrument used to measure the 
impact that pain has on the ability of a person to participate in essential life activities.  
Participants will rate their disability using a scale of 0 to 10 where 0 indicates no disability 
and 10, total disability.  
• 
QL Scores: QL (Quality of Life Questionnaire) and PedsQL18 is a brief, standardized, 
generic assessment instrument that systematically assesses adult patients and pediatric 
patients / parent’s perceptions of health-related quality of life (HRQOL) with chronic 
health conditions. The QL is based on a modular approach to measuring HRQOL and 
consists of a 15-item core measure of global HRQOL that includes physical, emotional, 
school and social domains of function  
• 
Time to return to sports, school and/or work in weeks 
  Other Independent Variables 
• 
Socio-demographic characteristics: Age and BMI, which will be reported as a continuous 
variable and sex, will be reported as a dichotomous variable. 
• 
Physical exam characteristics will be described as a categorical variable and classified as: 
Headaches (migrainous, cervicogenic/tension type, neuralgic or mixed) and / or axial neck 
pain (with extension, flexion, or extension and flexion) 

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• 
Presence of headaches, neck pain, or whole body pain before the intervention, which will 
be reported as a continuous variable in number of months. Concussion symptom scores 
will be collected using the Concussion Symptom Inventory, a symptom scale designed for 
tracking recovery/improvement from concussion headache.  
• 
Presence of psychological comorbidities such as anxiety and depression will be assessed 
over the course of the study using the Patient-Reported Outcomes Measurement 
Information System (PROMIS) Anxiety Symptoms Scale and the PROMIS Depressive 
Symptoms Scale Both scales have demonstrated reliability and validity, including internal 
consistency and convergent/divergent validity.  
• 
Presence of pain related comorbidities such as whole body pain, gastrointestinal problems, 
fibromyalgia and small fiber neuropathy will be classified as a categorical variable.  
• 
Presumed anatomic diagnosis will be described as a categorical variable and classified as: 
Facet arthropathy, occipital neuralgia, myofascial spams, spondyloysis, spondylolisthesis, 
axial, discogenic pain. 
F.  Data Collection Methods 
All patients will be assigned a unique personal identifier that will not be linked to any patient 
identifying information. Data will be collected during the study in case report forms and then will 
be entered into an Excel database, data form the email follow ups will be collected in REDCap 
and extracted and merged into the master Excel database.  
Research information collected during the study will be stored in locked cabinets with access 
limited to the Principal Investigator and research personnel affiliated with the study. All health 
information is protected by HIPAA (Health Insurance Portability and Accountability Act) and all 
health records will be kept confidential. Patients’ birthdate, name, and all other identifying 
information will be removed when analyzing and reporting on the data. Any personal identifying 
information will be stored separately from the other information the patient gives us and no 
personal identifying information will be reported in any publications or presentations. Identifying 
information will be kept in a password protected, secure file with limited access by research 
personnel. Once data collection is complete, identifying information will be destroyed. 
G. Data Management Methods 

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All relevant information retrieved from the electronic medical record, by the PI and/or a member 
of staff will be translated into an electronic form. Data collected in paper case report forms will be 
entered into a 21 CFR Part 11 compliant database, InForm Electronic Data Capture (EDC) 
Systems, for intake and checking, and will be protected by encryption and password. We will 
administer a baseline survey, followed by weekly or bi-weekly REDCap questionnaires that 
include information regarding post-procedure pain intensity scores, functional disability scores, 
anxiety and depression scores, and symptoms scores using REDCap questionnaires. The data 
obtained from these REDCap surveys will be maintained in the study’s REDCap database. 
REDCap is a secure, web-based application designed to support electronic data capture for 
research.  Only authorized users are permitted access to the data files, and daily server back-up 
activities are executed to ensure data recovery. All data will be stored on a password-secured 
research computer, and all data entered into the computers will be password protected.  Procedures 
to ensure accurate and reliable data collection will include well designed data forms and training.  
H. Quality Control Methods 
Data quality control will be assured through automated and manual methods. The study database 
enhances data quality through required entry fields for critical data and automatic flags for missing 
or out-of-range data. Efforts will be made to minimize data entry error by the development of a 
user-friendly database and all data entry will be double-checked with the source files.   
I. Data Analysis Plan and Sample Size 
At the time of data analysis, datasets will be downloaded from both REDCap and InForm and 
merged into Statistical Analysis Systems 9.3 for purposes of analysis. Missing data will be 
accounted for when the data is coded into respective variables.  
In order to detect a 30% difference between treatment groups, and with an α of 0.05 and β of 0.8, 
we will need a sample size of 24 subjects per group. Taking into consideration a 30% dropout rate 
during the study, we estimate a sample size of 63 subjects in the trial.  
We will analyze pain scores (NRS), MIDAS/ PedMIDAS, FDI and QL scores as continuous 
variables. Differences of these parameters from baseline will be the outcomes variables. The 
differences in pain, functional, and QL scores will first be tested for normality. Assuming 
normality, T-Tests will be conducted to investigate the differences between the two randomized 

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groups. If data does not appear to be normal, Wilcoxon Rank Sum Tests will be performed in 
contrast to T-Tests.  
Descriptive statistics will be generated in order to summarize socio-demographic characteristics 
of study participants. Frequency tables will be generated to describe gender, psychological and 
pain related comorbidities, history of injury, previous treatment methods and interventions. 
Similarly, frequency tables will be generated to depict physical exam characteristics, presumed 
anatomic diagnosis provided by clinicians, and presence of any predictive clinical findings. 
Continuous characteristics such as age and BMI will be tested for normality using the Shapiro-
Wilk test. Continuous characteristics will be summarized using mean and standard deviation if the 
distribution appears normal, or will be summarized using median and interquartile range if the 
distribution does not appear normal. We will evaluate baseline differences between responders and 
non-responders, using chi-square and t-test for categorical and continuous variables, respectively. 
Additionally, pain, functional, and QL scores will be assessed at multiple time points after 
treatment. Repeated measure analysis will be used to compare the pain, functional and QL scores 
over time between groups and compared with baseline values. We will also use multiple regression 
analysis where treatment, epidemiological, clinical, and psychosocial characteristics will be used 
as independent variables. Exploratory analysis comparing the two interventional groups will also 
be performed in order to generate future hypothesis of the best sequential treatment algorithm in 
PTH. 
The fluoroscopy time and radiation exposure amount will be checked for normality using the 
Shapiro-Wilk Test. If data is assumed to be normal, an analysis of variance will be conducted to 
assess difference in mean fluoroscopy time and radiation exposure amount. If data does not appear 
normal, a Kruskal-Wallis test will be performed.  
J. Adverse Event Criteria and Reporting Procedures 
Adverse or unanticipated events will be reported as required to the Boston Children’s Hospital and 
other site IRB’s according to institutional reporting requirements. An adverse event log will be 
used to document adverse events. 
An Adverse Event (AE) refers to any untoward medical occurrence associated with the use of 
Amitriptyline, whether or not considered drug related, as described in 21 CFR 312.32. We will 
monitor and report any AEs, as guided in 21 CFR 312.32. 

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The intensity (grade) of each AE will be assessed using the following scale: 
i. 
Grade 1 (Mild): Experiences which are usually transient, requiring no special treatment, 
and do not interfere with the subject's daily activities. 
ii. 
Grade 2 (Moderate): Experiences which introduce some level of inconvenience or concern 
the subject, and may somewhat interfere with daily activities, but are usually ameliorated 
by simple therapeutic measures (may include drug therapy). 
iii. 
Grade 3 (Severe): Experiences which are unacceptable or intolerable, significantly 
interrupt the subject's usual daily activity, and require systemic drug therapy or other 
treatment. 
iv. 
Grade 4 (Life-threatening): Experiences which cause the subject to be in imminent danger 
of death. 
v. 
Grade 5 (Death): Subject fatality 
If the intensity (grade) changes within a day, the maximum intensity (grade) should be recorded. 
If the intensity (grade) changes over a longer period of time, the changes should be recorded as 
separate events (having separate onset and stop dates for each grade). 
Relationship to the medication or procedure administration will be determined by the Investigator 
according to the following criteria: 
i. 
Unexpected/Expected Adverse Drug Events 
a. Unexpected: Any adverse experience, the nature, severity or frequency of which is 
not consistent with the the risk information described in the investigational plan or 
protocol or consent form.  Unexpected refers to an experience that has not been 
previously observed.  This includes events that are more serious than expected or 
occur more frequently than expected. 
b. Expected: Those experiences that have been identified in nature, severity, or 
frequency in the current investigator brochure, investigational plan/protocol and 
current consent form. 
ii. 
Relatedness  
a. Unrelated: The adverse event is clearly not related to the investigational agent  
b. Unlikely: The adverse event is doubtfully related to the investigational agent 
c. Possible: The adverse event may be related to the agent 

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d. Probable: The adverse event is likely related to the investigational agent 
e. Definite:  The adverse event is clearly related to the investigational agent 
For the purpose of safety analyses, all AEs that are classified as possible, probable or definite will 
be considered treatment-related events. 
We regard the following as AEs for ONB and CMBB procedures:  
• Neurotoxicity: The injection of anesthetics or steroids, or meningeal inflammation from 
the breech of the spinal canal during the procedure with or without direct neural injury can 
result in arachnoiditis or cauda equina syndrome. We regard these risks to be extremely 
low. 
• Neurological injury: Direct mechanical injury to the spinal nerves or the spinal cord itself 
can occur during needle placement for injections.  We regard these risks to be extremely 
low. 
• Vascular injury: Unintentional vascular injection of the steroid and local anesthetic 
suspension will result in medications simply being carried away from the site of 
inflammation, thus reducing any local anti-inflammatory effect. In contrast, intra-arterial 
injection is far less common, but may cause catastrophic neurologic injury and seizures.  
We regard these risks to be extremely low. 
• Pharmacologic effects of corticosteroids: The administration of exogenous corticosteroids 
can lead to both hypercortisolism and suppression of the adrenal cortex’s normal 
production of endogenous glucocorticoids. The long-acting corticosteroid preparations 
used for injections slowly release the active steroid over 1 to 3 weeks.  Fluid retention, 
weight gain, increased blood pressure and cushingoid side effects have been reported. 
Glucocorticoid administration reduces the effect of insulin and results in increased blood 
glucose levels and insulin requirements in diabetics for 48 to 72 hours.  
 Although 
rare, allergic reaction to systemic administration of corticosteroid has also been 
documented. We regard these risks to be extremely low. 
• Bleeding complications: Injections for pain treatment carries the risk of bleeding in patients 
without any apparent coagulopathy. Significant bleeding can cause compression of 
surrounding structures, potentially resulting neurological problems and worsening pain. 
We regard these risks to be extremely low. 

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• Infectious complications: Injection therapy for pain treatment carries a small risk of both 
superficial and deep infection, including neuraxial complications including sensory and 
motor deficits.  Other complications include osteomyelitis and septic arthritis of the facet 
joints. We regard these risks to be extremely low. 
In order to safeguard the privacy of patients, we have developed a mechanism for data and safety 
monitoring. A Data and Safety Monitoring Board (DSMB) will be established and will consist of 
2 members (see DSMB Plan and Charter). The PI will not be members of this board. All members 
of the DSMB will pay special attention to occurrence of AEs and SAEs.  
Reporting to the DSMB will occur if any 1 subject experiences a SAE as identified by the PI.  
Data and safety monitoring will be performed once per year by the DSMB.  
No individual care data will be reported unless there is a serious adverse effect. Reports will be 
done in an aggregated way.  
K.  Data and Safety Monitoring Plan 
The Data and Safety Monitoring Plan will focus on adequacy of data collection, and occurrence of 
serious adverse events. In the event of a DSMB review, the research information stored 
electronically and paper records will be available for examination by the DSMB and IRB as 
required.  Any serious adverse events that occur will be promptly reported to the Institutional 
Review Board according to IRB guidelines. A log will be used to document adverse events. The 
PI will review the safety and progress of this study on a regular basis.  All data will be collected 
in the strictest confidential manner and no personal identifiers will be recorded or included into 
the possible publication. All data will be protected by HIPAA (Health Insurance Portability and 
Accountability Act) and be stored electronically and maintained on a private folder in a password 
protected laptop/computer with limited access to investigators and research personnel affiliated 
with the study. After data analysis is complete any possible link to participants will be destroyed. 
The potential risks are limited, though as with any research participation, risk of breach of 
confidentiality exists.  
We have a licensed clinical psychologist included on this protocol that will review the anxiety and 
depression standard questionnaires of each participant and will contact those who score in the 
clinical range and provide referrals if necessary.  It is important to note that we will not be asking 

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any self-harm questions. Subjects who are found to need further attention will be referred to the 
appropriate services. 
L.  Risks and Discomforts 
The study treatments are part of the clinical standard of care for this patient population.  Some 
patients may experience known drug side effects, or pain, bruising and anxiety from treatment.  
However, we expect the risks to be minimal. Patients will be removed from the study at any point 
if the attending physician feels that treatment may be inappropriate to that patient’s care at that 
time or they develop any unexpected complications. The patient will be treated for any potential 
reactions. If a patient enrolled in the study should have an adverse event not typically associated 
with the study drug and the reaction is severe or life-threatening, then the investigator or the 
attending physician may choose to withdraw the patient from the study.  If this occurs, the patient 
will be withdrawn and unblinded and the IRB notified of the occurrence. 
For the interventional procedures such as the nerve block injections, the patient may receive 
sedation per physician’s discretion. If the patient requires sedation for the procedure we will inject 
drugs into the bloodstream generally using the intravenous route. We aim to reduce anxiety and 
pain, and achieve partial or total amnesia. The risks associated with sedation are an unconscious 
state, depressed breathing, and injury to blood vessels. We regard the likelihood of any side effects 
occurring from this procedure to be extremely low. 
M. Potential Benefits 
There is direct individual benefit given that the treatments in the study are part of clinical standard 
of care. Potentially, the information generated will strengthen the evidence base of medication 
management and interventional approaches in post traumatic headaches. 
Additionally, patients and families will be compensated for their time, possible expenses, and 
participation in the study in the form of a ClinCard Mastercard, a reloadable debit card. Patients 
could receive up to a maximum of $150 in compensation by the end of the study. Reimbursements 
will be distributed as follows: 
• $15 after the screening visit and nerve block injection;  
• $15 after the intitial two months, if patients complete more than 80% of the weekly follow-
up visits they will receive an additional $10; 

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• $30 after completing 6 months on the study, if patients complete more than 80% of the by-
weekly follow-up visits they will receive an additional $10; 
• $50 at the end of the study, 12 months after enrollment, if patients complete more than 80% 
of the by-weekly follow-up visits they will receive an additional $20. 
N.  Privacy Provisions 
All efforts will be made to ensure patient confidentiality. No patient identifiers will be used in the 
analysis or publications. 
O.  Confidentiality Provisions 
All identifying information such as dates of birth, names, and medical record numbers will be 
removed from the study database. All patients will be assigned to an ID number that will not be 
linked to any patient identifying information. Data collected for research purposes will not be 
entered into patient’s medical records. All data will be electronically secured in a password 
protected private folder. Only research investigators and personel affiliated with the study will 
have access to patient information.  
 
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18. Varni JW, Seid M, Rode CA. The PedsQL: measurement model for the pediatric quality of life 
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