Clinical trial NCT03447782
Conditions: New Daily Persistent Headache (NDPH)
Keywords: New Daily Persistent Headache Chronic Headache
Sponsor: Boston Children's Hospital
Start date: 2018-07-23; Completion date: 2020-11-20
Enrollment: 45 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
New daily persistent headache (NDPH) is a primary headache disorder characterized by the daily and unremitting headache pain patients experience with a distinct onset. Despite the known significant impairment associated with NDPH, the process by which some patients with NDPH recover within months while others do not is unknown.

The investigators propose to refine the clinical definition and suggest a novel mechanism underlying new daily persistent headache (NDPH) in adolescents. They further aim to investigate low-dose naltrexone for the treatment of new daily persistent headache. Healthy controls will also be enrolled in order to investigate the existence of a biomarker for NDPH. Adolescents ages 10-17 will be recruited from Boston Children's Hospital Pediatric Headache Program.

Detailed description:
The purpose of this study is to investigate low-dose naltrexone for the treatment of new daily persistent headache (NDPH) in adolescents ages 10-17. New daily persistent headache (NDPH) is a primary headache disorder characterized by continuous pain experienced for at least 3 months from distinct onset. Patients with NDPH have compromised academic performance, school absence, anxiety, depressed mood, sleep impairment, family disruption, and high health care costs. Despite the known significant impairment associated with NDPH, the process by which some patients with NDPH recover within months while others do not is unknown. With the goal of enhancing the clinical definition of NDPH, investigators will describe differences between patients with NDPH and healthy controls.

Additionally, little is known about which medications effectively manage and treat NDPH. One proposed medication that may benefit children and adolescents with NDPH is low-dose naltrexone. Naltrexone is an anti-inflammatory agent, similar to the opioid antagonist naloxone. Naltrexone is an effective treatment for opioid addiction, however, it was recently discovered that when taken in low doses (1/10 of the typical dose) naltrexone is capable of reducing the severity of chronic pain symptoms. By acting on glial cells in the nervous system as well as other receptors in the brain, naltrexone is capable of exerting analgesic effects. With this analgesic property, it has been speculated that low-dose naltrexone may be an effective treatment for the management of several chronic pain conditions, including headache.

Although more research must be conducted to evaluate long-term effects of using low-dose naltrexone, prior studies show that there are little short-term consequences associated with using this drug as a form of treatment for chronic pain symptoms. Investigators aim to assess the efficacy and safety of low-dose naltrexone in the treatment of patients with NDPH.

Arms: arm 1: Patients will be evaluated in clinic 1 month after the phone call evaluation. At this time, patients will begin a 3 month trial of low-dose naltrexone (Naltrexone HCL powder compounded to provide 4.5mg once per day orally).

Patients will be evaluated in clinic 3 months after beginning treatment with naltrexone. arm 2: These participants will be in the research study for the initial visit only. They will be evaluated by a physician or nurse practitioner
Interventions: intervention 1: Naltrexone HCl (Bulk) Powder
Intervention descriptions: intervention 1: For the NDPH Persistent group, patient will take naltrexone, 4.5 mg, po 1 time/day for three months-Naltrexone will be compounded from Naltrexone HCL powder

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
 
 
 
Endogenous Modulation and Central Sensitization 
in New Daily Persistent Headache in Children 
NCT03447782 
Date last reviewed by IRB: 8.3.2021 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
CHeRP IRB Additional Protocol Information: 
TITLE:  Endogenous Modulation and Central Sensitization in New Daily Persistent Headache 
(NDPH) in Children 
A. Specific Aims/Objectives  
Primary Aims 
Aim 1.1: Psychophysical Characterization of NDPH: To define differences in altered modulatory 
systems using offset analgesia as well as detailed clinical descriptors as part of a clinical evaluation 
and chart review in well characterized NDPH pediatric patients in the symptomatic and recovered 
state.  
 
We hypothesize that there will be significant differences and psychophysical parameters of 
offset analgesia between the symptomatic and recovered state. Specifically, there will be less 
pain inhibition as measured by the OA paradigm in the symptomatic patients.   
Aim 1.2: Treatment Effects in NDPH:  To define the effects of naltrexone on patients with NDPH 
using offset analgesia. 
 
We hypothesize that there will be significant differences in offset analgesia in the pre vs. post 
treatment groups. 
Aim 1.3: Comparing Offset Analgesia in NDPH patients to Healthy Controls: To determine 
whether the offset analgesia in patients with NDPH is impaired when compared to the OA responses 
of healthy controls included in IRB protocol (P00025596). 
 
We hypothesize that OA in patients with NDPH will be significantly impaired compared to the 
healthy controls. 
Secondary Aims 
Aim 2.1:  Laboratory Markers of Disease Persistence:  To define the potential of pain-related 
inflammatory markers in predicting disease persistence.  Specifically, a cytokine panel consisting of 
Interleukin 1 Beta, Interleukin 6, Interleukin 8, and Tumor Necrosis Factor will be collected for 
evaluation. 
 
We hypothesize that Inflammatory Markers will also define differences in responders vs. non-
responders. 


Aim 2.2: Brain Markers of Disease Resilience:  To evaluate brain markers of disease state through 
an evaluation of resting state endogenous modulatory systems (viz., cingulate -> PAG connectivity).   
 
We hypothesize that specific functional brain connectivity will define significant differences in 
modulatory systems (viz., Anterior Cingulate -> PAG Connectivity) in responders vs. non-
responders. 
Aim 2.3: Brain Markers of NDPH Compared to Healthy Controls: To compare the fMRI imaging 
and brain markers of patients with NDPH to healthy controls. 
Future Directions 
Genetic Analysis: To identify genetic variants associated with NDPH recovery vs. persistence, a 
single-nucleotide polymorphism (SNP) microarray will be designed based on known variants 
associated with chronic pain. Saliva samples will be collected during the first study visit, then de-
identified and stored for candidate gene association studies at a later time.  All HIPAA identifiers will 
be removed from the samples prior to analysis, and genetic data will be identified only by anonymous 
study ID. Individual results will not be returned to subjects/families.  
 
B. Background and Significance 
New daily persistent headache (NDPH) is a primary headache disorder with a reported 
prevalence of 3.5% in adolescents (Lipton et al., 2011). NDPH is characterized by the daily and 
unremitting headache pain patients experience with a distinct onset (IHS, 2013). Patients with NDPH 
have compromised academic performance, school absence, anxiety, depressed mood, sleep 
impairment, family disruption, and high health care costs (Baron & Rothner, 2010; Evans & Seifert, 
2011; Rabner et al., 2017). Despite the known significant impairment associated with NDPH, the 
process by which some patients with NDPH recover within months while others do not is unknown. 
With the goal of enhancing the clinical definition of NDPH, we will describe differences between 
patients with NDPH who recover within a few months and those who do not. 
Additionally, little is known about which medications effectively manage and treat NDPH 
(Rozen, 2014). One proposed medication that may benefit children and adolescents with NDPH is 
low-dose naltrexone. Naltrexone is an anti-inflammatory agent, similar to the opioid antagonist 
naloxone (Younger, Parkitny, & McLain, 2014). Naltrexone is an effective treatment for opioid 
addiction (Younger et al., 2014), however, it was recently discovered that when taken in low doses 
(1/10 of the typical dose) naltrexone is capable of reducing the severity of chronic pain symptoms 
(Younger, Noor, McCue, & Mackey, 2013). By acting on glial cells in the nervous system as well as 
other receptors in the brain, naltrexone is capable of exerting analgesic effects (Younger, Parkitny, & 
McLain, 2014). With this analgesic property, it has been speculated that low-dose naltrexone may be 
an effective treatment for the management of several chronic pain conditions, including headache.  
 
Low-dose naltrexone has the ability to mitigate pain symptoms in individuals with chronic pain. 
The effects of low-dose naltrexone on individuals with fibromyalgia have been extensively studied. In 
a pilot study conducted by Younger and Mackey (2009), when taken in low doses, naltrexone reduced 
self-reported daily pain and fatigue in patients with fibromyalgia. In an attempt to replicate these 
findings, Younger and colleagues (2013) again examined the effects of low-dose naltrexone in the 
treatment of fibromyalgia. Their study showed that, after a twelve-week period, women with 
fibromyalgia who were treated with naltrexone reported a reduction in pain in comparison to those 
who were treated with placebo (Younger, et al. 2013).   
Chopra and Cooper (2013) present two case studies in which low-dose naltrexone was used 
to treat Complex Regional Pain Syndrome (CRPS). Treating CRPS with naltrexone mitigated the 


symptoms in a 48-year-old male and eliminated the symptoms in a 12-year-old female, with notably 
no side effects from taking low-dose naltrexone in either case (Chopra and Cooper, 2013). Low-dose 
naltrexone has also been used to treat pain associated with Crohn’s disease with promising outcomes 
(Smith et al., 2007). Per self-report diary over a three month period, low-dose naltrexone was found to 
greatly decrease symptoms associated with the disease and increase quality of life in a sample of 
patients 18-years and older (Smith, et al., 2007). Although more research must be conducted to 
evaluate long-term effects of using low-dose naltrexone, prior studies show that there are little short-
term consequences associated with using this drug as a form of treatment for chronic pain symptoms.  
We aim to assess the efficacy and safety of low-dose naltrexone in the treatment of patients with 
NDPH. 
C. Preliminary Studies  
This will be a new project with no ongoing research in patients with NDPH. Use of OA and fMRI 
imaging are currently investigated in other patient populations at BCH, including in healthy control 
populations and will be used to compare with the NDPH sample from this protocol (OA data - 
P00025596; fMRI data - P00019376). 
D. Design and Methods  
(1) 
Study Design 
The sample size will include 150 participants, consisting of 100 patients with NDPH 
and 50 healthy controls (non-headache patients) visiting the Pediatric Headache Program, 
ages 10-17 years old.  Eligible patients will be identified from a review of medical records for 
patients returning to the Pediatric Headache Program for follow-up care. Age and gender 
matched healthy controls will be recruited from the greater Boston area, including siblings of 
patients, children from local schools, children previously enrolled in other BCH studies as 
healthy controls, and per advertising per wall brochures, Craig’s list, and per the MBTA in 
Boston. 
The design is both cross-sectional and longitudinal as different participants will 
participate in the study for different amounts of time.  Healthy controls will participate in only 
one visit while patients with NDPH will participate in two or three visits.  The study contains 
three components: study visits and evaluations, a naltrexone trial, and an imaging component.  
All participants will undergo the initial evaluation, with NDPH participants participating in one to 
two other evaluations.  Study visits include a physical and neurological evaluation, a blood 
draw, and an evaluation utilizing offset analgesia. Participants with NDPH will begin a trial of 
low-dose naltrexone at Visit 3. The trial will last for three-months and conclude at Visit 4.  
Select participants with NDPH will also complete the imaging component consisting of an fMRI 
brain scan.  See “Study Timeline” section for complete details on each task and when they will 
occur. 
Of note, it was particularly challenging to recruit healthy controls for this study, 
particularly due to the COVID-19 pandemic. Because healthy control data is such a valuable 
part of this study in order to better understand how the NDPH population differs from typical 
adolescents, healthy control OA data from P00025596 and healthy control fMRI data from 
P00019376 will be used to compare with the NDPH sample data. 
 (2) 
Patient Selection and Inclusion/Exclusion Criteria  
Eligibility criteria include: 1) Patients meeting clinical ICHD-3-Beta classification for 
NDPH; 2) Age 10-17 years, all sexes, races, and ethnicities; 3) English speaking; 4) Able to 
wean off headache prophylactic medication 2 weeks prior to start of Naltrexone trial (patient 


will still be able to use abortive medication throughout the duration of the study); on stable 
psychotropic medication for mild anxiety and/or mood disturbance for 2 weeks.   
Exclusion criteria include: 1) Children and adolescents with significant chronic medical 
illness: CNS (secondary headache disorder other than mild TBI); Cardiac, Pulmonary other 
than stable asthma, Metabolic, Renal, Hepatic; 2) Significant psychiatric disorder, such as 
major depression, somatization disorder, and psychosis; 3) Pregnancy; 4) Intellectual delay or 
cognitive limitations precluding completion of questionnaires or following instructions. 
(3) 
Description of Study Treatments or Exposures/Predictors  
o Low-dose naltrexone: Participants with persistent NDPH will once daily take 4.5mg of 
naltrexone orally for three months. 
 
Naltrexone is an anti-inflammatory agent, similar to the opioid antagonist 
naloxone.  Naltrexone is an effective treatment for opioid addiction (Younger et 
al., 2014), however, it was recently discovered that when taken in low doses 
(1/10 of the typical dose) naltrexone is capable of reducing the severity of 
chronic pain symptoms (Younger et al., 2013).  A similar drug, 
methylnaltrexone, has indications for use in children with opioid induced 
constipation. 
(4) 
Definition of Primary and Secondary Outcomes/Endpoints  
Primary Outcomes  
1. A change in pain intensity scores and headache frequency- The NRS, numerical rating 
scale will be used, with a pain score between 0 to 10, with 0 being no pain and 10 
being worst pain imaginable, for NDPH patients, chronic and recovered, completing 3 
months of naltrexone, as compared to a cohort of patients with NDPH on standard 
treatment. 
2. A difference in response (self-reported pain intensity-NRS) regarding heat pain 
between NDPH patients, chronic and recovered, and controls using the OA paradigm. 
3. A difference in laboratory testing, including inflammatory markers, in patients with 
NDPH, chronic and recovered, and controls, indicating a difference in modulatory tone.  
4. A difference in default network connectivity in NDPH patients, chronic and recovered, 
and controls.  
Secondary Outcomes  
1. A change in functional disability scores - The functional disability inventory (FDI) will be 
used to assess differences in disability pre- and post-naltrexone treatment, as well as 
between recovered and persistent patients. 
2. A change in self-perceived pain sensitivity - The Pain Sensitivity Questionnaire (PSQ) 
will be used to assess differences in pain sensitivity pre- and post-naltrexone 
treatment, as well as between recovered and persistent patients. 
 (5) 
Data Collection Methods, Assessments, Interventions and Schedule (what 
assessments performed, how often)  
Offset Analgesia:  
Offset analgesia will be examined by applying a 3-tempeature paradigm described previously 
validated in adults volunteers, using individualized test temperatures to ensure that children 
are not exposed to greater than moderate heat pain, defined as a rating of 50mm out of 
100mm on an electronic visual analog scale (eVAS). Testing will be completed using the 


Medoc TSA-2001 device (Medoc Ltd. Advanced Medical Systems, Ramat Yishai, Israel). The 
thermal sensory analyzer operates by a microcomputer-driven 3 cm x 3 cm (9 cm2) Peltier 
contact thermode. The entire thermode- stimulating surface is placed in contact with the skin 
on the volar surface of the non-dominant forearm and secured by a Velcro band without 
stretch. The thermode baseline temperature is kept at 320C (room temperature) and 
stimulation temperature has a potential range of 0–500C for safety reasons. A preset 
computer-controlled temperature paradigm is programed to deliver a specific temperature 
patterns. During all tests, patients will rate heat pain intensity continuously in real time using 
the linear, electronic visual analogue scale (eVAS). Patients will use their dominant hand to 
operate sliding knob of the eVAS with the following two anchors on 0 to 100 mm line. The left 
endpoint designated as “no pain sensation” (0 mm) and the right endpoint as “most intense 
pain sensation imaginable” (100 mm). Patients will be instructed to move the slider in 
proportion to their pain intensity in real time during testing.  
 
Testing Procedures 
On the day of testing and after obtaining consents from a guardian and assent from the child, 
a single researcher will perform all sensory tests in a quiet room, temperature 20–230C, with 
the patient comfortably seated or reclined, and the non-dominant forearm skin site will be 
exposed to ambient temperature for 10–15 min before testing. Patients will not be permitted to 
view the QST computer screen. The volar forearm will be divided into three zones and the 
probe will be moved to a new zone for each test with 2-3 min breaks between tests to avoid 
adaptation and sensitization of the skin. Prior to testing, children will be exposed to 2-3 training 
stimuli of 42-440C for 5 seconds to familiarize themselves with the stimulus and electronic 
VAS. Then, patients will participate in a test to determine the individualized test temperature 
that will be used for dynamic, constant and control tests. 
 
1. Identification of the individualized test temperature: First, individualized test 
temperatures for the offset analgesia paradigm will be determined. We will determine 
the lowest temperature that evokes moderate pain, defined as an eVAS score of 50mm 
on a scale of 0mm (no pain) to 100mm (most intense pain sensation imaginable). This 
is equivalent to a score of 5 on a scale of 0-10 on a numeric rating scale, i.e., 50% of 
maximal heat pain perceived by individual patients. Each temperature stimulus will be 
held for 5 seconds, and then return to room temperature for 30 seconds before the 
next temperature is applied. The first temperature stimulus will be set to 420C (a 
median threshold for heat pain detection temperature i.e., at 50th percentile for children 
ages 7-15 years). Then the temperature will be increased by 10C increments, every 30 
seconds until the lowest temperature that evokes an eVAS of 50mm is achieved. The 
maximum temperature will be set to 490C. Thus, if a temperature of 490C does not 
evoke moderate pain (50 mm rating on a scale of 0-100 mm  on the electronic VAS) in 
a patient or healthy control subject the test will be terminated to avoid potential skin 
burn and patient or subject will be excluded from this study procedure. With this 
method of testing, no patient or subject will be exposed to more than what they 
perceive as moderate pain. We previously found that the normal reference interval for 
heat pain threshold (the point at which mild pain is felt) for children ages 6-17 years is 
39 – 460C (25th – 75th percentiles) and 35.6 – 50.00C (2.5th - 97.5th percentile), and 
thus we begin our assessment of test temperatures at the median threshold of 420C.  
 
2. Response to a Dynamic Test Stimulus:  A reduction in self-reported pain intensity 
when the test temperature is applied for 5 seconds, raised by 10C for 5 second, 
reduced by 10C, and held for 20 seconds. Pain is assessed throughout the test in real 
time using the computerized eVAS. This test will be completed three times.  
 
3. Response to a Controlled Stimulus on forearm skin:  A reduction in self-reported 
pain intensity when the test temperature is applied for 5 seconds, raised by 10C for 5 
second, reduced to 320C, and held for 20 seconds. Pain is assessed throughout the 
test in real time using the computerized eVAS. This test will be completed three times. 


 
4. Response to a Constant Test stimulus on forearm skin:  A reduction in self-
reported pain intensity when the test temperature is applied at a constant rate for 30 
seconds. Pain is assessed throughout the test in real time using the computerized 
eVAS. This test will be completed three times. 
Questionnaires: 
1. Functional Disability – The Functional Disability Inventory (FDI; Claar & Walker, 2006) 
assesses children's self-reported difficulty in physical and psychosocial functioning due 
to their physical health.  The measure consists of 15 items concerning perceptions of 
children’s activity limitations during the past two weeks. Children rate these activities 
on a 5-point scale ranging from 0 (“No trouble”) to 4 (“Impossible”), and total scores are 
computed by summing the items.  Scores on the FDI range from 0 to 60, with higher 
scores indicating greater disability. 
 
2. Pain Sensitivity – The Pain Sensitivity Questionnaire (PSQ; Ruscheweyh et al., 2012) 
is a 17-item measure where respondents answer how painful a daily life situation would 
be for them. Items are rated on a scale ranging from 0 (“not painful at all”) to 10 (“worst 
pain imaginable”). 14 of the items ask about situations that the majority of healthy 
subjects would rate as painful (e.g., bump your elbow on the edge of a table; burn your 
tongue on a hot drink). Three items describe situations that are normally not rated as 
painful by healthy subjects (e.g., taking a warm shower). These items are interspersed 
between the “painful” items to serve as non-painful sensory reference for the subjects 
and are not included in the total score. 
 
 (6) 
Study Timeline (as applicable) 
As the study timeline differs between participant groups, we have outlined the specific timeline 
for each group. 
Participants who are healthy controls: 
These participants will be in the research study for the initial visit only. The visit will last 2 
hours and consist of the activities noted in the table below for “Visit 1: Initial Evaluation.” 
Following consent, participants will be briefly evaluated by a physician or nurse practitioner as 
part of a routine neurological and physical exam.  They will then be evaluated using offset 
analgesia.  Next, they will be asked to collect a saliva sample and complete a few 
questionnaires on pain sensitivity and functional disability.  Finally, participants will have blood 
drawn (no more than 15ml) from one arm.  There are no follow up visits for healthy controls 
and they will receive their compensation for participating in the study before they leave the 
hospital. 
Due to trouble in recruiting healthy controls, particularly as a result of the COVID-19 pandemic, 
we will use the OA healthy control data from IRB protocol P00025596 and fMRI healthy control 
data from IRB protocol P00019376 in order to compare the NDPH patients to healthy controls.  
Participants with New Daily Persistent Headache: 
Participants with NDPH will be in this research study for about 4-7 months. The table below 
details the full timeline of participants completing the entire study. It is important to note that of 
those 7 months, they will only take the drug, low-dose naltrexone, for 3 months.  


The first visit will last 2 hours and consist of the activities noted in the table below for “Visit 1: 
Initial Evaluation.” Following consent, participants will be briefly evaluated by a physician or 
nurse practitioner as part of a routine neurological and physical exam.  They will then be 
evaluated using offset analgesia. Next, they will be asked to collect a saliva sample and 
complete a few questionnaires on pain sensitivity and functional disability.  Finally, participants 
will have blood drawn (no more than 15ml) from one arm.   
The next visit will consist of a phone call lasting no more than 15-minutes that covers the 
activities noted in the table below for “Visit 2: 3 Month Post Initial Evaluation.” On this call, 
participants will discuss their current headache health with a member of the research team.  
Based on this conversation, participants will be categorized into two groups: “improved” or 
“persistent”.  Both groups will return for the next visit one month later.  “Improved patients” will 
continue their current care, however, “persistent” patients will wean off all daily/preventative 
medication for the next month prior to the third visit. 
Participants with NDPH who are categorized as “Improved”: 
The third visit will last 2 hours and consist of most of the activities noted in the table below for 
“Visit 3: 1 Month Post Phone Call.” The visit will start with a brief evaluation by a physician or 
nurse practitioner as part of a routine neurological and physical exam.  Participants will then 
complete a few questionnaires on pain sensitivity and functional disability and again be 
evaluated using offset analgesia.  Finally, they will have blood drawn (no more than 15ml) from 
one arm.  This will conclude the visit for most participants.  A portion of “improved” participants 
will randomly be selected to participate in the imaging component of the study on the same 
day as the third visit (timeline detailed in section “Imaging Component Participants”). 
Participants with NDPH who are categorized as “Persistent”: 
The third visit will last 2 hours and consist of most of the activities noted in the table below for 
“Visit 3: 1 Month Post Phone Call.” The visit will start with a brief evaluation by a physician or 
nurse practitioner as part of a routine neurological and physical exam.  During this meeting, 
the physician or nurse practitioner will discuss the trial of low-dose naltrexone and instruct the 
participant on when to take it. They will then complete a few questionnaires on pain sensitivity 
and functional disability and again be evaluated using offset analgesia.  Finally, they will have 
blood drawn (no more than 15ml) from one arm.  This will conclude the visit for most 
participants.  A portion of “improved” participants will randomly be selected to participate in the 
imaging component of the study on the same day as the third visit (see section “Imaging 
Component Participants”). 
The fourth and final visit will last 2 hours and consist of the activities noted in the table below 
for “Visit 4: 3 Month Post Visit 3.” The visit will start with a brief evaluation by a physician or 
nurse practitioner as part of a routine neurological and physical exam.  Participants will then 
complete a few questionnaires on pain sensitivity and functional disability and again be 
evaluated using offset analgesia.  Finally, they will have blood drawn (no more than 15ml) from 
one arm.  This will conclude the study for all participants. 
Imaging Component Participants: 
A selection of participants will randomly be selected to participate in the imagine component of 
the study on the same day as the third visit (referred to in the table below as “Visit 3: 1 Month 
Post Phone Call”).  The imagine component will add an additional 45 minutes to the visit and 
consist of a routine, resting state fMRI brain scan. fMRI healthy control data from IRB protocol 
P00019376 will be used in order to compare the fMRI data for NDPH patients to healthy 
controls.  


 
Study Visit 
Timeline (NDPH) 
Visit 1: 
Initial 
Evaluation 
Visit 2: 
3 Month Post Initial 
Evaluation (Phone Call) 
Visit 3: 
1 Month Post 
Phone Call 
Visit 4:  
3 Month 
Post Visit 3 
Consent /Assent 
X 
 
 
 
Physical/Neurological 
Exam 
X 
 
X 
X 
Offset Analgesia 
X 
 
X 
X 
Saliva Sample 
X 
 
 
 
Questionnaires  
X 
 
X 
X 
Blood Draw 
X 
 
X 
X 
Medication Changes 
 
X (Possible end of 
prophylactic/daily 
medication) 
X (Start of 
Naltrexone) 
X (End of 
Naltrexone) 
MRI (only for a portion of 
participants) 
 
 
X 
 
E. Adverse Event Criteria and Reporting Procedures  
There are potential adverse events associated with naltrexone. Some commonly reported side 
effects include anxiety, nervousness, trouble sleeping, headaches, abdominal cramping, diarrhea, 
gastrointestinal distress, nausea, irritability, loss of appetite, drowsiness, joint stiffness, and 
nasopharyngitis (common cold). Taking naltrexone while using high doses of opioids can cause 
serious injury, coma, or death. Patients will be advised of all of these adverse events in the consent 
form and again prior to receiving naltrexone during Visit 3.  Patients will also be advised to report any 
adverse events to the research team and in the case of a serious reaction to call 911 and/or proceed 
to the emergency room. 
It is important to note that these are the potential adverse events associated with naltrexone 
administered at its normal dosage, and not in a low-dose which will be taken in this study.  Prior 
studies detailing the use of low-dose naltrexone have reported adverse events related to sleep (i.e., 
insomnia, more vivid dreams), nausea (Smith et al., 2007; Younger & Mackey, 2009; Younger et al., 
2013) and in one study headaches (Younger et al., 2013). One case series reported no adverse 
events (Chopra & Cooper, 2013).  If a participant reports an adverse event, the PI and the Data and 
Safety Monitoring Board (DSMB) will both be immediately notified.  The PI will speak with the 
participant and, depending upon the severity of the adverse event and the participant’s desire, discuss 
the continuation or termination of their participation in the study. 
It is also possible that an abnormal finding may be found on an fMRI. If this occurs, Dr. LeBel 
(PI) will call or meet with the participant to discuss the findings and refer the family to the proper 
Boston Children’s Hospital service if needed. 
Additionally, due to the neurological/physical examination and the questionnaires 
administered, there is a possibility that a participant may become distressed. If this occurs, they will 
be given the option of stopping the study. Dr. LeBel (PI) and staff psychologist, Dr. Kaczynski (co-PI), 
will be available by page and phone for consultation regarding any participant that may be 
experiencing distress. Should additional mental health support be required, patients and families will 
be referred to the appropriate Boston Children’s Hospital service.  If there is any indication of risk for 
harm to self or others, a risk assessment will be conducted and a mental health clinician will decide on 
the best course of action to ensure the safety of the child or parent. To deal with potential discovery of 


child abuse, the Child Protection Team at Children's Hospital will be consulted and a 51-A filed in 
accordance with that consultation. 
F. Data Management Methods  
All patients will be assigned a unique identifier that will not be linked to any patient identifying 
information. Data will initially be collected in case report forms and then entered into a secure 
REDCap database. Any research information collected during the study on paper forms will be stored 
in locked cabinets with access limited to the PI and research personnel associated with the study. All 
health information is protected by HIPAA (Health Insurance Portability and Accountability Act) and all 
health records are kept confidential. Patient’s birthdate, name, and all other identifying information will 
be removed when analyzing and reporting the data. Any personal identifying information will be stored 
separately from other information the patient provides and no personal identifying information will be 
reported in any publications or presentations. Identifying information will be kept in a password 
protected and secure file with limited access by research personnel. Once data collection and 
compliance mandates are complete, identifying information will be destroyed. 
Due to trouble in recruiting healthy controls, particularly as a result of the COVID-19 pandemic, 
we will use OA healthy control data from IRB protocol P00025596 and fMRI healthy control data from 
IRB protocol P00019376 in order to compare the NDPH patients to healthy controls. The PI’s of those 
two protocols are also co-investigators of this protocol and will internally run the analyses from the two 
respective datasets, and only aggregated post-comparison results will be shared with the study team. 
No de-identified data will be shared or compared in any way between protocols. 
 
G. Quality Control Method  
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. All data entry will be double checked with source files. QST testing for OA will 
be monitored by Dr. Sethna, senior researcher in QST methodology. fMRI data will be monitored by 
Dr. Borsook, senior investigator in Pain Imaging. 
H. Data Analysis Plan  
 
We will analyze pain scores (NRS), FDI and PSQ scores as continuous variables. Differences 
of these parameters from baseline will be the outcomes variables. The differences in pain, FDI, and 
PSQ scores will first be tested for normality. Assuming normality, t-tests will be conducted to 
investigate the differences between the two randomized 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 
calculated 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 including pain duration, previous treatment methods and interventions. Similarly, frequency 
tables will be generated to depict physical exam characteristics. 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 those with persistent NDPH, with recovered NDPH and healthy 
controls across various outcome measures (pain intensity, headache frequency, FDI, PSQ) as well as 
OA and inflammatory markers, using chi-square and t-test for categorical and continuous variables, 
respectively. Additionally, differences in the same measures will also be assessed pre- and post-
naltrexone treatment. 


 
I. Statistical Power and Sample Considerations  
In order to detect a moderate effect in the difference in pain scores pre- and post-naltrexone 
treatment, with an α of 0.05 and a β of 0.8, we will need a sample size of 50 subjects per group. With 
the consideration of NDPH subject dropout, we estimate a sample size of 160 subjects in total, 55 per 
NDPH group and 50 controls. We propose 3 years for completion, including imaging. 
J. Study Organization  
Not applicable as data will only be collected at the Pediatric Headache Program, located in the 
Waltham satellite location of Boston Children’s Hospital. The PI (Alyssa LeBel, MD) is the director of 
the clinic and will provide oversight and guidance for all study participants and personnel.   
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