Mindfulness and Mechanisms of Pain Processing in Adults With Migraines
Phase: NA
Conditions: Migraine
Sponsor: Wake Forest University Health Sciences

Official Title:  Mindfulness and Mechanisms of Pain Processing in Adults With Migraines
NCT02695498
Date: 2/19/2020

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Title: Mindfulness and Mechanisms of Pain Processing in Adults with Migraines 
 
Principal Investigator:  Rebecca Erwin Wells, MD, MPH, Assistant Professor, Department of 
Neurology, Wake Forest University Health Sciences  
 
Supported by: The National Center for Complementary and Integrative Health (NCCIH): 
K23 AT008406-01A1 
 
Study Intervention Provided by: N/A 
 
Sponsor of IND (IDE): N/A 
 
Study Team Roster 
Rebecca Erwin Wells, MD, MPH 
Don Penzien 
Tim Houle (Massachusetts General Hospital) 
Robert Coghill (Cincinnati Children’s Hospital) 
Russ Phillips 
Suzanne Danhauer 
Elizabeth Loder 
 
Study Site 
Wake Forest School of Medicine 
Department of Neurology 
Wake Forest Translational Science Clinical Research Unit 
 
 
OVERVIEW: 
Part 1 of this study is a cross-sectional study evaluating the pain responses of migraineurs 
compared to healthy controls.  Part 2 is a randomized clinical trial of Mindfulness Based Stress 
Reduction in migraineurs.  Part 1 will include both healthy volunteers and migraineurs while Part 
2 will only include migraineurs.  Migraineurs may participate in both parts of the study. 
 
The protocol is split into Part 1 and Part 2.   
 
PART 1 
 
PRÉCIS  
 
Title: Mindfulness and Mechanisms of Pain Processing in Adults with Migraines 
 
Primary Objective of this study:  Assess experimental heat pain responses (pain intensity, pain 
unpleasantness, pain catastrophizing, emotional reactivity) in migraineurs vs. healthy controls.  
 
Design and Outcomes 
To accomplish this objective, we will conduct a cross-sectional study in migraineurs (interictally, 
i.e., between migraine attacks) and healthy controls to compare responses to experimental heat 
pain intensity and unpleasantness and correlate these results to differences in emotional 
reactivity and pain catastrophizing. 

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Outcomes: Stimulus-response curves will be generated for each subject using the logarithmic 
equation: log (VAS pain ratings)=log (t – 35) * coefficient + intercept where t represents stimulus 
temperature.1 The coefficient and intercept generated for heat pain intensity and heat pain 
unpleasantness will both be used as outcome variables, as well as scores from the Pain 
Catastrophizing Scale (PCS)2, and the Difficulty in Emotion Regulation Scale (DERS).3   
 
Interventions and Duration 
Participants will complete ONE study visit where they will complete the PCS and DERS 
instruments and will complete Quantitative Sensory Testing (QST) pain measurements.  We will 
compare responses to experimental heat pain intensity and unpleasantness on both 
migraineurs and healthy controls to compare and correlate these results to differences in their 
emotional reactivity and pain catastrophizing. 
Sample Size and Population 
 
The subject population consists of 98 participants (49 migraineurs and 49 healthy controls) who 
will be recruited for Part I.  Participants will be of any gender and ethnicity.  Migraineurs will be 
recruited through the Department of Neurology, Internal Medicine, Family Medicine, and the 
Emergency Department from Wake Forest School of Medicine. In addition, recruitment will 
occur from Dr. Timothy Houle’s Headache research program, via Wake Forest’s electronic 
medical record system, advertisements/flyers and the Downtown Health Plaza (DHP). Healthy 
Controls will be recruited from the greater Winston-Salem area through IRB-approved local 
flyers (posted at the four local colleges, including Wake Forest University), advertisements 
placed online (e.g. Craigslist) and in local newspapers (e.g. the Winston-Salem Journal), and 
through the Wake Forest Baptist Hospital institutional database of research volunteers.  
Interested persons will contact the study staff for a telephone screen. A study cell phone will be 
set up so that interested persons can call at any time. The phone will be secured and encrypted 
via our AirWatch Mobile Device Management solution. 
 
All referring providers will be invited to a presentation to thank them for their assistance and to 
present the data results from the study. At the presentation, the referring providers will be 
entered into a drawing for a $100 gift card whether the referred subject enrolls in the study or 
not. 
 
To ensure comparable groups, migraineurs and controls will be matched on age (±5 yrs), 
gender, and race.   
STUDY OBJECTIVES 
Primary Objective 
Primary Objective of this study:  To assess experimental heat pain responses (pain intensity, 
pain unpleasantness, pain catastrophizing, emotional reactivity) in migraineurs vs. healthy 
controls.  
 
Hypotheses: Migraineurs will report higher pain intensity and pain unpleasantness levels in 
response to experimentally induced pain than controls; (1b): Pain catastrophizing and emotional 
reactivity will moderate the association between pain unpleasantness and pain intensity; (1c): 
Pain catastrophizing and emotional reactivity scores will be positively associated with pain 
unpleasantness levels. 

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BACKGROUND AND RATIONALE 
Background on Condition, Disease, or Other Primary Study Focus 
Migraine is common and disabling. Migraine affects 36 million Americans and costs $15 
billion/year due to lost workdays, diminished productivity, and increased health care utilization.4-
6 Affective/cognitive processes such as pain catastrophizing and emotional reactivity often play 
a major role in migraine pain and disability and may be just as important to target as the sensory 
aspect. High pain catastrophizing, a maladaptive cognitive process of exaggerated pain 
rumination,7-11 is associated with more pain and disability across clinical pain syndromes, 
including headache.12-21 Affective disturbance is highly comorbid with migraine and associated 
with migraines becoming chronic.22-25 Due to this cognitive/affective load that builds over time in 
migraine, we hypothesize that migraine alters the relationship between the sensory and 
affective dimensions of pain processing. 
Study Rationale 
Our current tools of migraine pain measurement are inadequate to distinguish the overall 
burden of suffering, as there is an over reliance on a single numerical pain score to represent 
the entire pain experience.  For example, one patient with a level 8/10 migraine pain may still be 
functioning at work while another may be writhing in bed at home, completely disabled.  
Measuring and targeting the affective component, in addition to the sensory component of pain, 
may capture this discrepancy in disease burden. In the chronic pain world, distinguishing 
between the sensory and affective components of pain has yielded useful insights.  For 
example, cancer pain is impacted by high affective pain ratings while musculoskeletal pain has 
much lower affective pain ratings. Interestingly, this work has not been extended into the 
migraine world, as though migraine pain is viewed as a purely sensory pain experience. If 
affective mechanisms are, in fact, more important than previously realized, this could explain the 
excess burden of migraine in people with comorbid affective conditions like anxiety, depression, 
and with past histories of emotional or sexual abuse. The affective component of migraine pain 
may be just as important as the sensory component to target and measure since it significantly 
impacts outcomes, disability, and has therapeutic treatment implications.  
 
Quantitative sensory testing (QST) is a robust lab paradigm (not a clinical experience) that 
delivers one painful noxious thermal stimuli and asks for simultaneous pain intensity and pain 
unpleasantness scores. By using this in our research, we will be able to differentiate the sensory 
(pain quality—what the pain feels like) from the affective (how awful/unpleasant the pain feels) 
components of experimental pain in normal controls vs. migrainuers. If there is a difference 
between QST measurements in healthy controls vs. migraineurs, an intervention’s impact could 
be determined if it brings migraineurs’ QST results closer to healthy controls’ QST results. QST 
results could become a marker of migraine activity. Affective components of pain may be 
targeted in ways that do not involve medication, which is highly desirable in a condition that is 
persistent throughout a lifetime and principally affects women of childbearing potential. In 
summary, distinguishing the sensory from affective components of pain in our research will help 
us determine if QST measurements can be used as a marker of migraine activity. 
 
Migraineurs may process noxious stimuli differently than healthy non-migraineurs,26 but we do 
not fully understand this difference. Using acute experimental pain in adults with clinical 
headache pain may help us understand the cognitive and affective mechanisms involved in both 
types of pain processing. This study will help disentangle the sensory (pain intensity) and 
affective (pain unpleasantness) components that comprise the subjective pain experience and 
we will be able to compare these components in migraineurs vs. healthy controls.   
 
We hypothesize that having migraine affects the relationship between the sensory and affective 
dimensions of pain processing, and this relationship is moderated by these affective/cognitive 

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factors that build over time in migraineurs (e.g., pain catastrophizing and emotional reactivity). 
We will assess this hypothesized difference directly by evaluating pain intensity (sensory 
component of experimental pain) and unpleasantness (affective component of experimental 
pain). Interestingly, migraineurs exhibit lower thermal pain and tolerance thresholds, lower 
mechanical pain thresholds, enhanced pain expectation, and deficits of conditioned pain 
modulation and habituation.26-32 When compared to healthy controls, we hypothesize that: 
(Figure 1) A)  migraineurs will exhibit significantly higher pain reports in response to 
experimentally induced pain; B) pain catastrophizing and emotional reactivity will moderate the 
association 
between pain 
unpleasantness and pain intensity; and C) the affective/cognitive factors (Figure 1, Box A) will 
be positively associated with pain unpleasantness.  
 
 
 
 
 
 
No previous studies have evaluated differences in experimental pain intensity vs. pain 
unpleasantness in migraineurs vs. controls. As migraine pain uniquely involves many altered 
sensory phenomenon (e.g., photophobia, phonophobia), it cannot be assumed that responses 
to experimental pain in migraine will be the same as other clinical pain syndromes. Further, 
different clinical pain syndromes have distinct responses to pain intensity vs. pain 
unpleasantness.33     
STUDY DESIGN 
We will conduct a cross-sectional study in migraineurs (interictally, i.e., between migraine 
attacks) and healthy controls to compare responses to experimental heat pain intensity and 
unpleasantness and correlate these results to differences in emotional reactivity and pain 
catastrophizing.  
SELECTION AND ENROLLMENT OF PARTICIPANTS  
Inclusion Criteria 
Inclusion criteria for Healthy Controls: ≥18yo; pain free and healthy, without any major medical 
or psychiatric conditions 
Inclusion Criteria for Migraineurs: ≥18yo with >1 yr of migraines and currently 4-20 days/month 
with migraines, although no migraine the day of study visit (see Table 1 for migraine diagnosis) 
or pain relieving medications within 12 hours of study visit.  
Exclusion Criteria 
Exclusion criteria for Healthy Controls: Diagnosis of migraine, probable migraine, Current 
regular (weekly or more often) practice of meditation or other mind-body intervention 
or frequent headaches of any type other than tension-type headaches on three or fewer 
days/month. 
Figure 1  
Theoretical Model of Experimental Pain Responses in Migraineurs. 
H1a, H1b, and H1c refer to the corresponding Hypotheses from Aim 1 
Affective/Cognitive Factors
Pain Catastrophizing
Emotional Reactivity
Pain 
Unpleasantness
Pain
Intensity
Box A
Migraine
H1b
H1c
H1a

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Exclusion criteria for both: Any major unstable medical/psychiatric illness (e.g., hospitalization 
within 90 days, suicide risk, etc.); severe clinical depression/anxiety (with PHQ-9 scores >20); 
chronic pain condition (e.g., fibromyalgia, migraines for healthy controls, etc.) or sensory 
abnormalities (e.g., neuropathy, Raynaud’s, etc.); current regular (weekly or more often) 
practice of meditation or other mind-body intervention; diagnosis of medication overuse 
headache or chronic migraine. Migraineurs will be studied if they have been headache-free the 
day of the study visit.  Participants may be currently taking migraine medications, as long as 
they do not have a diagnosis of medication overuse headache. Volunteers with no pain ratings 
to frankly noxious stimuli (temperatures > 49°C) or excessive responses to threshold 
temperatures (~43°C) will be excluded. Pregnant subjects will be excluded from all portions of 
the study due to possible unknown risks of frankly noxious stimuli.  Due to unknown risks and 
potential harm to the unborn fetus, sexually active women of childbearing potential must use a 
reliable method of birth control while participating in this study. Reliable methods of birth control 
are: abstinence (not having sex), oral contraceptives, intrauterine device (IUD), DepoProvera, 
tubal ligation, or vasectomy of the partner (with confirmed negative sperm counts) in a 
monogamous relationship (same partner). An acceptable, although less reliable, method 
involves the careful use of condoms and spermicidal foam or gel and/or a cervical cap or 
sponge. 
 
Table 1: Migraine Diagnosis* 
 At least 5 attacks, not attributable to another disorder, with: 
 Headache lasting 4-72 hours (untreated or unsuccessfully treated) 
 Headache with at least 2 of the 4: 
 Unilateral location 
 Pulsating quality 
 Moderate or severe pain intensity 
 Aggravation by or causing avoidance of routine physical activity (e.g. 
walking or climbing stairs) 
 During headache at least 1 of the 2: 
 Nausea and/or vomiting 
 Photophobia and phonophobia 
*According to the International Classification of Headache Disorders-II Guidelines 
Study Enrollment Procedures  
The subject population consists of 98 participants (49 migraineurs and 49 healthy controls) who 
will be recruited for Part I.  Participants will be of any gender and ethnicity.  To ensure 
comparable groups, participants and controls will be matched on age (±5 yrs), gender, and race. 
We have obtained IRB approval for all recruitment procedures (Wake Forest IRB protocol # 
IRB00027845). 
Participants with migraines will be recruited through several different mechanisms 1) Wake 
Forest Departments of Neurology, Internal Medicine, Family Medicine and Emergency 
Department; 2) Wake Forest Houle Headache Research Center 3) Wake Forest Electronic 
Medical record system;  4) Local flyers, radio/television/newspaper advertisements.  The 
primary source of recruitment will be through the Wake Forest Department of Neurology clinics.   
 
The primary source of recruitment will be through the Wake Forest Department of Neurology 
clinics.  Dr. Wells has her own headache clinic within the department, where she has seen over 
300 headache patients in the last year (on average 9 new and 6 follow-up patients per week).  
Patients will also be recruited through the Wake Forest primary care clinics. Flyers will be 
placed throughout the hospital and specifically in the clinics of Neurology, Internal Medicine, 
OB/Gyn, and Family medicine and in the Emergency Department.  On average, Wake Forest 
sees >800patients/year in the Emergency Department with a diagnosis of migraine.  

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Presentations made to medical students, residents, and faculty at Wake Forest in these 
departments to further inform clinicians about the trial and invite them to refer eligible patients.  
Further, four research assistants are available through the WF emergency department and 
actively screen patients 6 days/week, 18 hours/day (108 hours/week).  The Houle Headache 
Research Center has a successful record of recruiting headache patients for clinical research, 
recruiting 3-5 headache patients/week over the last 5 years.  Wake Forest has a newly 
implemented electronic record system, “WakeOne” (an Epic program), and with IRB approval, 
we can query our Translational Data Warehouse for all patients seen at Wake Forest with a 
diagnosis of migraine (ICD-9 code 346) and then be able to securely have access to their data 
to be able to contact them.  Conducting such a search reveals 17,494 records of patients with a 
diagnosis of migraines seen at Wake Forest in the past five years.  Finally, we will use multiple 
local advertising mechanisms to recruit participants, such as local newspapers (e.g. Winston 
Salem Journal), magazines (Forsyth Woman, etc.) local National Public Radio service, local 
television network stations, press releases, and social media (Facebook, etc.). For adults with 
migraines, “opt-out” letters will be sent to potential participants and then they will be contacted 
by study staff for a telephone screen.   
 
Healthy Controls will be recruited from the greater Winston-Salem area through IRB-approved 
local flyers (posted at the four local colleges, including Wake Forest University), advertisements 
placed online (e.g. Craigslist) and in local newspapers (e.g. the Winston-Salem Journal), and 
through the Wake Forest Baptist Hospital institutional database of research volunteers.   
 
Screening Process-Telephone Screen:   
A study investigator will contact interested participants for a pre-screening telephone interview.  
At the beginning of the phone call, potential subjects will be informed of the nature and 
sensitivity of the questions, asked whether this is an appropriate time for them to answer these 
questions, and told how long the phone call is expected to take.  Participants will be offered the 
option of completing the pre-screening in person, if they wish and if it is feasible.  The pre-
screening telephone interview will be performed to explain the protocol, determine eligibility, 
discuss informed consent, and answer questions.  If eligible, they will then be offered 
participation.  Those interested and eligible will be either immediately scheduled for a screening 
visit or will be called in the future to set it up.  A letter will then be sent to them, with the consent 
form attached for review ahead of time if they would like, in advance of their study visit. 
 
Consenting procedures: 
We will obtain consent before the experiment begins at the study visit. At the onset of the study 
visit, participants will be provided informed consent by the PI or a qualified study team member. 
The consenting process will occur in a private clinic room. Subjects will be given time to ask 
questions and can discuss with family members.  The consent form states the title and purpose 
of the study, an estimate of how many people may enroll, the duration of participation, the 
procedures that will be followed, any reasonably foreseeable risks or discomforts, and benefits 
to the participants or others that may be expected from the research.  Information is provided 
about the disclosure and confidentiality of protected health information they will provide, that 
there is no cost to participants in the study, who sponsors the study, what happens if they 
experience an injury or illness as a result of participating, and whom to call if they have a 
question or problem. Participants will be informed of payment ($40 for completion of the study 
visit). The telephone number of the Chairman of the Institutional Review Board will also be 
included for questions regarding rights as research subjects. The consent form will be signed 
and dated by the participant and by the person obtaining consent.  The consent form has been 
approved by Wake Forest IRB (IRB protocol # IRB00027845). 
Screening 
Screening evaluations that will occur at the study visit for inclusion/exclusion include: 
 
Full Neurology evaluation to confirm diagnosis and inclusion/exclusion criteria 

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STUDY INTERVENTIONS  
Interventions, Administration, and Duration  
There will only be ONE study visit, which will have 3 parts. 
Study Visit (Parts A, B, C): 
Part A: Participants will meet with a member of the study team to: 1) review study protocol; 2) 
obtain informed consent; 3) obtain detailed health history/exam to confirm inclusion/exclusion 
criteria.  
 
Part B: Psychological Measures: Before the experimental session, participants will use 
REDCap to complete the questionnaires (see Table 6 for migraineurs and Table 7 for healthy 
volunteers).   
 
Part C: Experimental Session of Quantitative Sensory Testing (QST) Measurements: 
Thermal Probe: MEDOC TSA-II will deliver thermal stimuli with a 16 x 16 mm thermal probe. All 
temperatures will be < 50°C and no stimulus as designed produces tissue damage. We have 
significant experience using this technique and probe with no adverse events (Coghill’s lab on > 
750). 
 
Psychophysical Training: To gain experience rating pain, subjects will be familiarized with 32, 5-
second duration stimuli (35 to 49°C) with the Visual Analogue Scale (VAS), a 15 cm plastic 
sliding scale used to quantify pain sensation intensity and degree of unpleasantness. 37 The VAS 
is an ideal pain measurement scale because of its ratio scale properties combined with its ease 
of administration and scoring.38 The minimum rating is “no pain sensation” or “not all 
unpleasant” whereas the maximum is designated as “most intense imaginable” or “most 
unpleasant imaginable.” The training will be conducted on the left arm, a location away from 
increased sensitivity/allodynia of head/neck regions often seen in patients with migraines.   
 
Pain Threshold Assessment:  The temperature of the probe will begin at 32°C and will increase 
at a rate of 0.5°C per second. The subject will be instructed to verbally respond when he or she 
first detects a sensation of pain. The thermode will return to baseline once the button is pressed. 
This will be performed up to four times, and the heat pain threshold will be determined as the 
average of the temperatures at which the stimulus was first perceived as painful (Yarnitsky and 
Sprecher, 1994). Stimulus temperatures employed for pain threshold testing will not exceed 
50°C. This will be conducted on the right arm. 
 
Experimental Session: We will administer the noxious thermal stimulation on the right calf by 
starting at 35°C and increasing with a 6°C rise/fall rate with a 5 second plateau up to the 
randomly administered temperatures of 43, 45, 47, and 49°C. Each temperature will be 
repeated x 3 and delivered pseudorandomly. To minimize sensitization, habituation, and 
hyperalgesia, all trials will be separated by 30 seconds and systematically distributed over the 
calf to minimize repetitive stimulation of the same skin site.1,37,39  Perception of intensity and 
unpleasantness will be measured with the VAS scale after each temperature. Each series will 
be repeated twice. Dr. Wells has been trained in the performance and analysis of QST 
measurements.  
 
The specified arm/leg positioning of the probe may be adjusted if needed. 
Handling of Study Interventions  
N/A 

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Concomitant Interventions  
Allowed Interventions 
Participants may continue all current treatments for their migraines while participating in 
this study.   
Required Interventions 
To participate in the study, patients must not currently have a migraine at the time of the 
study visit; migraineurs will be studied if they have been headache-free the day of the study 
visit. If participants arrive at the study visit and actively have a headache, they will be re-
scheduled for completion of the study visit when headache-free.   
Prohibited Interventions 
N/A 
Adherence Assessment  
The survey assessments will be completed using REDCap and study personnel will ensure 
all questions are answered before participants leave each session. Study personnel will 
also be conducting the QST pain assessments so adherence to both pain testing and 
survey assessments will be high.   
STUDY PROCEDURES  
 
Table 2- Summary of Schedule of Evaluations-Part I 
 
Task 
Telephone Screen 
Study Visit 
Confirm Eligibility 
X 
X 
Review Study Protocol 
X 
X 
Sign Informed Consent 
Form 
 
X 
Health history/exam to 
confirm inclusion/exclusion 
criteria  
 
X 
Complete Questionnaires 
 
X 
QST Measurements 
 
X 
 
QST: Quantitative Sensory Testing 
Description of Evaluations-See above in Study Enrollment Procedures and Study 
Interventions 
SAFETY ASSESSMENTS  
Experimental Heat Pain Assessments:  The quantitative sensory testing may cause brief 
pain, but all temperatures will be < 50°C and no stimulus as designed produces tissue damage. 
The thermal probe used for this experiment, MEDOC TSA-II, will deliver thermal stimuli with a 
16 x 16 mm thermal probe.  The pain stimuli are chosen so that most people can tolerate them.  
These stimuli have been used for many years with no harmful physiological or psychological 
complications. However, the heat may cause redness of the skin for up to several hours, but 
does not cause any blistering. 

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The subject can easily pull away from the device if the feeling is not tolerable. The laboratory 
staff are experts in conducting the heat-pain intervention and the temperature of the thermal 
heat probe will be monitored at all times.  Dr. Coghill’s lab has conducted this procedure on over 
750 participants and no serious adverse events have been associated with this device.  A 
computer controlled device that touches the skin is used to apply the heat used for sensory 
testing.  In extremely rare cases, the computer controlled stimulator has been reported to 
malfunction and to cause a burn to the small skin region being tested.  Since this device will not 
be strapped to the participant’s leg or arm, the participant can easily pull away from this device 
and stop stimulation at any time.   
 
Reporting Procedures 
We will promptly report any unanticipated problems, serious and unexpected adverse events, 
deviations or protocol changes to the IRB and Data Safety and Monitoring Board (See Data 
Safety and Monitoring Board for more details). 
 
Serious adverse events (SAEs) that are unanticipated, serious, and possibly related to the study 
intervention will be reported to the I-DSMB, Wake Forest School of Medicine IRB, and NCCIH in 
accordance with requirements. 
 
Unexpected fatal or life-threatening AEs related to the intervention will be reported to the NCCIH 
Program Officer within 7 days. Other serious and unexpected AEs related to the intervention will 
be reported to the NCCIH Program Official within 15 days. 
 
Anticipated or unrelated SAEs will be handled in a less urgent manner but will be reported to the 
I-DSMB, Wake Forest School of Medicine IRB, NCCIH, and other oversight organizations in 
accordance with their requirements. In the annual AE summary, the I-DSMB Report will state 
that they have reviewed all AE reports. 
 
The WFSM Institutional Data & Safety Monitoring Board (I-DSMB) will monitor the study for 
purposes of evaluating participant safety and study integrity. The I-DSMB is a Dean-appointed, 
multi-disciplinary, standing committee that is available to provide independent oversight for 
human research studies conducted by WFSM or by WFSM-affiliated faculty investigators. The 
board will review the progress of and safety for the study on a regular basis as seen below in 
the table 3. The DSMB will meet to review safety data at least once annually while the study has 
active participants, even if the prespecified review targets, as specified above, have not been 
met. There will be no fee for the independent monitoring of the study. All protocol deviations and 
adverse events will be promptly reported to the I-DSMB as well the IRB. See DSMB plan for 
more details. 
 
Table 3-Safety Reporting of Data 
 
Data type 
Frequency of review 
Reviewer 
Subject accrual (including 
compliance with protocol 
enrollment criteria) 
Quarterly 
PI, DSMB 
Status of all enrolled subjects, 
as of date of reporting  
Quarterly 
PI, DSMB 
Adherence data regarding 
study visits and intervention 
Bi-annually 
PI, DSMB 
AEs  
Bi-annually 
PI, DSMB 

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Data type 
Frequency of review 
Reviewer 
SAEs 
Per occurrence 
PI, DSMB, NCCIH 
STATISTICAL CONSIDERATIONS  
General Design Issues  
Hypothesis 1a: Adults with migraines will have a greater response to experimental pain than 
healthy controls. 
Hypothesis 1b: Adults with migraines will have higher levels of pain unpleasantness after 
controlling for pain intensity compared to controls. 
Hypothesis 1c: Adults with the highest pain catastrophizing and emotional reactivity scores will 
have the highest levels of pain unpleasantness. 
Sample Size and Randomization 
Sample Size Calculation: Using the marginal benefit formula for repeated measures 
(Vickers),40 and assuming an average within-person correlation between repeated 
measurements of 0.5, a sample size of 48/group will give us 80% power to detect an effect size 
as low as d=0.62 for the group main effect (Hypotheses 1a and 1b).  Thus, if the average VAS 
rating in the controls is 3 (±2 SD), we will be able to detect a VAS rating of 4.24 in migraineurs; 
smaller differences are unlikely to have clinical significance.  For hypothesis 1c, 98 participants 
will also give us 84% power to detect a bivariate correlation of at least 0.4 between pain 
catastrophizing scores or emotional reactivity scores and pain unpleasantness levels (r≤0.4 not 
likely of clinical significance).  
Outcomes  
Stimulus-response curves will be generated for each subject using the logarithmic equation: log 
(VAS pain ratings)=log (t – 35) * coefficient + intercept where t represents stimulus 
temperature.1 The coefficient and intercept generated for heat pain intensity and heat pain 
unpleasantness will both be used as outcome variables, as well as scores from the PCS and the 
DERS. 
Data Analyses  
Statistical Analyses: We will use mixed effects hierarchical regression models with a 
distribution and link function appropriate to the outcome (e.g., the best fitting distribution as 
defined by model selection). Repeated measures within each participant (i.e., experimental trials 
within a session) will be handled using subject-level random effects.  We do not expect missing 
data for this Aim, given the controlled nature of the experimental session and electronic data 
capture. The specific analyses are outlined for each hypothesis: 
 
Analyses 1a: We will separately regress the individual pain outcomes (pain intensity, pain 
unpleasantness) on the factorial effects for group (migraine, control), stimulus (43, 45, 47, and 
49 C), and repeated experimental block (1, 2, and 3). Absent any higher order two-way (e.g., 
group x stimulus) or three-way (e.g., group x stimulus x block) interaction involving group, we 
will interpret a statistically significant group main effect as evidence that the two groups differ in 
their experimental pain reports.    
 
Analyses 1b: We will run the same model as 1a but exclusively using pain unpleasantness as 
the outcome. We will add pain intensity as a predictor, to “control” for pain intensity reports. In 
this way, we will examine group differences in pain unpleasantness after controlling for pain 
intensity ratings (i.e., do the groups differ in degree of unpleasantness after accounting for the 
sensory aspect of the stimulus?)      

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Analyses 1c:  We will regress pain unpleasantness on stimulus, block, and pain intensity 
ratings, but will also add catastrophizing and emotional reactivity scores as subject-level 
predictors. A statistically significant effect for the predictor (catastrophizing or emotional 
reactivity) will be interpreted as support for an association between the predictor and outcome 
(pain unpleasantness).    
DATA COLLECTION AND QUALITY ASSURANCE 
Research material obtained from human subjects (specimens, records, data).   
The study data will be collected and managed using REDCap electronic data capture tools 
hosted at Wake Forest School of Medicine.41  REDCap (Research Electronic Data Capture) is a 
secure, web-based application designed to support data capture for research studies, providing: 
1) an intuitive interface for validated data entry; 2) audit trails for tracking data manipulation and 
export procedures; 3) automated export procedures for seamless data downloads to common 
statistical packages; and 4) procedures for importing data from external sources. 
PARTICIPANT RIGHTS AND CONFIDENTIALITY  
Institutional Review Board (IRB) Review  
 
Informed Consent Forms 
IRB approval of these procedures has been obtained (IRB protocol # IRB00027845). Prior to 
participating in any phase of these studies, informed consent will be obtained from all subjects 
by personnel directly associated with this study. All procedures and risks will be fully explained 
to subjects. Informed consent from healthy subjects will be indicated/documented by the 
subject’s signature on a consent form. Subjects will also receive a copy of the consent form. 
Subjects will be recruited for studies via postings on campus, Internet advertisements, and other 
printed advertisements in the community. If necessary to obtain adequate minority 
representation, under-represented racial groups will be targeted specifically for recruitment. 
 
Participant Confidentiality and Data Storage 
Confidentiality will be protected by collecting only information needed to assess study 
outcomes, minimizing to the fullest extent possible the collection of any information that could 
directly identify subjects, and maintaining all study information in a secure manner. Storage of 
all data will be electronically entered on a password protected network drive. To help ensure 
subject privacy and confidentiality, only a unique study identifier will appear on the data 
collection form. All question and answers will be recorded by research assistants, placed in 
confidential subject folders, and stored on a separate master log. Any collected patient 
identifying information corresponding to the unique study identifier will be maintained on a 
separate master log. The master log will be kept secure, with access limited to designated 
study personnel. Following data collection subject identifying information will be destroyed at 
the earliest opportunity, consistent with data validation and study design, producing an 
anonymous analytical data set. Data access will be limited to study staff. Data and records will 
be kept locked and secured, with any computer data password protected. No reference to any 
individual participant will appear in reports, presentations, or publications that may arise from 
the study. 
 
Per copyright agreement for the Social Connectedness Scale-Revised (SCS-R), the PI has 
agreed to send de-identified results of the SCS-R and basic demographics to the author of the 
measure for possible secondary data analysis. 
 
Conflict of Interest: There are no conflicts of interest. 
Benefits to Participants 

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This study does not present the prospect of direct benefit to the participants. However, the study 
will provide the opportunity to gain a better understanding of how migraine affects pain 
processing. 
 
PUBLICATION OF RESEARCH FINDINGS 
We plan to publish our findings in top-tier scientific, peer-reviewed journals.  
 
 
PART 2 
PRÉCIS  
Objectives  
Primary objective: Test the impact of MBSR in adults with migraines on clinical headache pain. 
 
Secondary Objectives: Test the impact of MBSR in adults with migraines on experimental heat 
pain, mindfulness, pain acceptance, pain catastrophizing, emotional reactivity, and headache-
related disability compared to an education control group; determine factors that predict MBSR 
response on migraine pain. 
 
Design and Outcomes   
We will conduct a prospective, randomized controlled trial in 98 adults with migraines 
randomized to either MBSR or a migraine/stress education control group to assess the impact 
of MBSR on the sensory and affective aspects of clinical and experimental pain in adults with 
migraines and to determine predictors of clinical efficacy 
 
Interventions and Duration  
Participants will be randomized to either an Mindfulness Based Stress Reduction Course 
(MBSR) or an Education control group; both will meet weekly for 2.5 hours for 8 weeks, and 
may be assigned daily homework of approximately 30 minutes/day.  MBSR is a standardized 
course in mindfulness mediation and yoga and the control group will be educated about 
migraine pathophysiology, headache triggers, stress, gentle stretches, and daily migraine 
readings. The goal of the control group is to match the time/attention/expectation of the MBSR 
group, without providing key ingredients of mindfulness meditation or yoga. The control group 
will be taught by a health care provider trained in headache care.   
 
Sample Size and Population  
 
98 adults with migraines will be randomized 1:1 to either MBSR or the education control group.  
Migraineurs will be recruited through the Department of Neurology, Internal Medicine, Family 
Medicine, and the Emergency Department from Wake Forest School of Medicine. In addition, 
recruitment will occur from Dr. Timothy Houle’s Headache research program, via Wake Forest’s 
electronic medical record system, advertisements/flyers and the Downtown Health Plaza (DHP) 
STUDY OBJECTIVES 
Primary Objective 
Primary objective: Test the impact of MBSR in adults with migraines on clinical headache pain. 
 

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Secondary Objectives 
Secondary Objectives: Test the impact of MBSR in adults with migraines on experimental heat 
pain, mindfulness, pain acceptance, pain catastrophizing, emotional reactivity, and headache-
related disability compared to an education control group; determine factors that predict MBSR 
response on migraine pain. 
BACKGROUND AND RATIONALE 
Background on Condition, Disease, or Other Primary Study Focus 
Migraine is common and disabling, affecting 36 million Americans and costing $15 billion/year 
due to lost workdays, diminished productivity, and increased health care utilization.4-6 
Affective/cognitive processes such as pain catastrophizing and emotional reactivity often play a 
major role in migraine pain and disability and may be just as important to target as the sensory 
aspect. Due to this cognitive/affective load that builds over time in migraine, we hypothesize 
that: A) migraine alters the relationship between the sensory and affective dimensions of pain 
processing; and B) therapies like Mindfulness-Based Stress Reduction (MBSR) that target these 
factors may be especially beneficial and may differentially influence the affective component of 
migraine. MBSR is a standardized course in mindfulness meditation and yoga with beneficial 
effects on many health outcomes,42 including chronic pain.43-49  
Study Rationale 
Meditation differentially decreases affective (i.e., pain unpleasantness) over sensory (i.e., pain 
intensity) dimensions of experimental pain50-56 and reduces pain by engaging brain regions 
important for the cognitive and affective modulation of pain.51,53,55-57 Our pilot trial demonstrated 
the safety, feasibility, and beneficial effects of MBSR on migraines.58 MBSR may prevent 
migraines by decreasing emotional reactivity (e.g., affective responses to stress), 59-63 and stress 
is a well-known migraine trigger.64-66 MBSR may also train migraineurs to practice non-
judgmental awareness of sensory events, reducing the affective dimension of pain more than 
the sensory component, and this effect may be greater in those with a greater affective pain 
component. By measuring both experimental and clinical pain, we will be able to test these 
hypotheses. Further, understanding predictors of response would improve clinical utility. 
Affective components of pain may be targeted in ways that do not involve medication, which is 
highly desirable in a condition that is persistent throughout a lifetime and principally affects 
women of childbearing potential. Research has demonstrated that meditation, a non-
pharmacological intervention, differentially decreases the affective over sensory responses to 
experimental pain in healthy controls.  After learning to meditate, one’s experience of pain is 
altered, with diminished affective responses to pain. We will be able to evaluate this effect in the 
clinical pain condition of migraine by determining if a meditation intervention taught to 
migraineurs differentially decreases the affective responses over the sensory responses to 
experimental pain. This work will be a novel contribution that demonstrates the specific 
mechanisms of meditation-induced pain relief in migraine patients. In summary, distinguishing 
the sensory from affective components of pain in our research will help us determine if QST 
measurements can be used as a target for treatment. This ultimately will help us further 
understand the mechanisms of meditation induced pain relief and allow for more precise, 
targeted treatment options.   
 
Further, medications alone rarely target the affective/cognitive processes that often play a major 
role in migraine pain and disability. Because of this high affective/cognitive burden of migraine 
pain, we hypothesize that therapies that target these factors may be especially beneficial and 
may differentially impact the affective component of migraine pain. For example, cognitive 
behavioral therapy (CBT) is efficacious (with Grade A evidence) for migraine prevention. 67-70 

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Mindfulness-Based Stress Reduction (MBSR) has beneficial effects on many health outcomes, 
including chronic pain conditions.42-49,71-74 MBSR is a standardized course in mindfulness 
meditation and yoga.75 Mindfulness meditation involves both 1) focused attention on a sensation 
like the breath while non-judgmentally disengaging from distracting thoughts; and 2) open 
monitoring, with non-reactive present-moment awareness of sensory stimuli.76 These practices 
cultivate a detached observation of sensory experiences like pain,49,74 which may alter the pain 
experience, resulting in less pain unpleasantness, pain catastrophizing, emotional reactivity, 
and more pain acceptance.45,59,60,62,63,77 The active mental training of meditation may also foster 
a non-reactive approach to life stressors. This may decrease emotional reactivity (e.g., affective 
responses to stress),59-63 thereby decreasing the likelihood of triggering a migraine from stress 
(a common migraine trigger).64-66 Further, meditation differentially decreases affective (pain 
unpleasantness) over sensory (pain intensity) response to experimental pain 50-56 and engages 
brain regions important for the cognitive and affective modulation of pain.51,53,55-57,78,79 Based on 
this research and the models developed by Jensen,80 Day et al,81 and Price,82 we created a 
simplified theoretical model of mechanisms of migraine pain relief from MBSR (Figure 2). By 
targeting affective/cognitive factors (Figure 2, Box A), we hypothesize that MBSR: A) prevents 
migraines from occurring, decreasing migraine frequency; B) decreases the affective 
components of pain so even when migraines do occur, pain unpleasantness is attenuated; and 
C) decreases migraine disability. (Figure 2). We will test these hypotheses directly by 
measuring both experimental and clinical pain.  
 
 
 
 
MBSR also requires time, energy, and healthcare resources. Thus, identifying predictors of 
response is critically important to better target and tailor MBSR to treat migraine. For instance, 
pain acceptance and pain catastrophizing were the most important factors of treatment 
response of a mindfulness-based cognitive therapy for headache.83 Since mindfulness 
meditation appears to selectively target these processes, we hypothesize that those with the 
highest baseline levels of pain catastrophizing, emotional reactivity, and the affective 
component of experimental pain will be most likely to respond to MBSR. Increases in pain 
acceptance and mindfulness and decreases in pain catastrophizing and emotional reactivity 
may be associated with decreases in clinical and experimental pain and disability after MBSR.  
 
No previous studies have used experimental pain to evaluate mechanisms of meditation on 
migraine. Measures of pain intensity and pain unpleasantness will assess nociceptive 
processing distinct from clinical pain status, providing a means to determine if clinical pain is 
differentially susceptible to reduction by MBSR. Further, employing experimental pain 
methodologies will allow us to distinguish affective from sensory processing, allowing us to test 
our hypotheses that MBSR reduces the affective more than the sensory experience, and this 
effect will be greater among patients with a greater affective component to their pain. 
 
We will be able to determine predictors of MBSR response in migraineurs. Identifying simple 
and inexpensive ways to evaluate response will allow treatments to be targeted to those most 
likely to benefit.   
Figure 2  
Theoretical Model of MBSR Mechanisms of Migraine Pain Relief 
MBSR
Affective/Cognitive Factors
Mindfulness
Pain Acceptance
Pain Catastrophizing
Emotional Reactivity
Pain Unpleasantness
Pain Intensity
Pain Intensity
Box A
Migraine Frequency
Migraine 
Disability

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PRELIMINARY STUDIES   
We conducted several epidemiological studies that showed that many adults with neurological 
conditions, including headaches, use complementary and alternative medicine, despite a lack of 
evidence.84-89 Further, in adults with migraines/severe headaches in the US, the mind-body 
therapies of deep breathing, meditation, and yoga are the most commonly used. 88 However, 
there have only been a few prior studies with non-standardized meditation and yoga 
interventions in migraine.90-92 We conducted 2 randomized controlled trials (RCT) of MBSR that 
demonstrated the safety, feasibility, and efficacy of MBSR in adults with mild cognitive 
impairment93,94 and migraines.58 In 19 adults with migraines randomized to either MBSR (n=10) 
or usual care (n=9), MBSR demonstrated no adverse events, 0% dropout, excellent adherence 
(daily meditation average: 34±11 minutes; class average: 6/8 sessions), and promising effect 
sizes across several outcomes, despite being a pilot trial without adequate power (Table 4).58 
Theme analyses from qualitative interviews revealed that MBSR may also decrease emotional 
reactivity and improve pain cognitive reappraisal processes (e.g., less pain catastrophizing and 
more pain acceptance). The methods of this pilot trial58 will be applied to this research.  The 
results from this study support future studies with larger sample sizes to evaluate mechanisms. 
 
 
Table 4: Improvements* in MBSR vs. Control Group after MBSR in Adults with Migraines 
 
M easure 
Change in M BSR vs. 
Control, df 
95% CIg 
 
Comment 
Headaches 
 
 
Although underpow ered, migraines w ere: 
  Frequency of Migraines/month 
-1.4      d=0.32 
[-4.6, 1.8] 
   -less frequent in MBSR group 
  Severity (0-10 scale) 
-1.3      d=0.61 
[-2.3, 0.1] 
   -less severe in MBSR group 
  Duration (hours) 
-2.9      d=0.75 
[-4.6, 0.02] 
   -shorter duration in MBSR group 
Headache Disability Scores 
 
 
 
  MIDASa 
-13       d=1.37 
[-22, -1] 
Headache disability decreased in MBSR group 
  HIT-6b 
-5c        d=0.91 
[-11, -1.0] 
Headache disability decreased in MBSR group 
Additional Measures 
 
 
 
  Self-Efficacyd 
+13      d=0.81 
[1, 30] 
Self-efficacy improved in MBSR group 
  Mindfulnesse 
+13      d=0.80 
[3, 26] 
Mindfulness improved in MBSR group 
 
*Pilot study w as not pow ered to see differences on these outcomes; a-Migraine Disability Assessment (MIDAS), 
range: 0-5 (minimal), 6-10 (mild), 11-20 (moderate), >21 (severe); b-Headache Impact Test-6 (HIT-6), Range 36-
78, 60+: severe impact; c-A change of 2.3 points on HIT-6 reflects the minimum important difference that reflects 
meaningful clinical change; d-Headache Management Self Efficacy scale, Range 0-175; e-Five-Facet Mindfulness 
Scale, Range 0-195; f=Cohen’s d; g-Confidence Interval 
 
STUDY DESIGN 
We will conduct a prospective, randomized controlled trial in 98 adults with migraines 
randomized to either MBSR or an education control group. All participants will have migraines 
(no healthy controls).   
 
 
 
SELECTION AND ENROLLMENT OF PARTICIPANTS 
 
 

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Table 5: Inclusion Criteria & Exclusion Criteria 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Enrollment Procedures  
Recruitment:  We will recruit 7 participants every 3 months over the 42 month recruitment 
period. The study will be run in 6 cohorts. Once ~16 participants meet criteria via phone 
screening, they will be re-evaluated at the in-person screening visit (see below) to ensure they 
still meet inclusion criteria. After the screening visit, they will begin keeping their 4 week 
Inclusion criteria 
Diagnosis of Migraine (see Table 1) 
4-20 days/month with migraines 
≥1 year of migraines 
≥18 years 
Able and willing to participate in 8 weekly 
sessions and possible daily homework 30-
45min 
Exclusion criteria 
Current regular (weekly or more often) 
practice of meditation or other mind-body 
intervention 
Any major unstable medical/psychiatric illness 
(e.g., hospitalization within 90 days prior to 
screening, suicide risk, etc.)  
Other non-migraine chronic pain condition 
(e.g., fibromyalgia, low back pain, etc.) or 
sensory nerve problems (e.g., neuropathy, 
Raynaud’s, etc.)  
Diagnosis of medication overuse headache 
(International Classification of Headache 
Disorders-II) 
Volunteers with no pain ratings to frankly 
noxious stimuli (temperatures > 49°C) or 
excessive responses to threshold 
temperatures (~43°C) 
Current or planned pregnancy or 
breastfeeding 
Any new medication started within four weeks 
of screening visit 
Unwilling to maintain stable current 
medication dosages for duration of trial 
Failure to complete baseline headache logs 
Figure 3:Part 2 Research 
 Telephone 
 Screen 
  SCREENING VISIT 
 -Consent 
 -Neurology evaluation 
 -Questionnaires 
 -QST measurements 
 -Migraine logs begun 
 
Follow-up: 3 & 6 mo 
-Questionnaires 
-QST measurements  
  
Initial Follow-Up 
-Questionnaires 
-QST measurements 
-Qualitative interview  
Randomization 
MBSR 
Education 
Control  
Group 
Recruitment 

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headache log (see below); once completed, final determination of inclusion and randomization 
will occur. Recruitment will continue until sample size goals are reached. We will assume ~10% 
dropout (conservative estimate given our 0% dropout rate in our pilot trial), so will aim to recruit 
98 participants for a final sample of 88 participants. (There may be some overlap of the 
migraineurs with Part 1).   
 
Screening Visit: The study staff will consent participants, confirm migraine diagnosis with 
history/neurological exam (will include Structured Diagnostic Interview for Headache), and have 
participants 1) confirm that no pain relieving medications within 12 hours of study visit, 2) 
complete baseline questionnaires if they have not been completed at home; 3) complete 
quantitative sensory testing (QST) as described in Part 1; and 4) learn how to capture daily 
migraine information using REDCap electronic data capture tools (or iPod touches for those 
without internet access). Participants will track migraines x 4 weeks to 1) confirm diagnosis; 2) 
confirm ability to log daily; and 3) use as the 4 week “pre-trial” baseline migraine data.  
 
Randomization: Once 4-week migraine logs are reviewed by study staff to ensure eligibility, 
participants will be randomized 1:1 to either MBSR or the control group, stratified by migraine 
frequency (low frequency of 4-9 headaches/month or high frequency of 10-20 
headaches/month). Treatment assignments will be generated by a permuted blocks method 
with randomly varying block size and sealed in numbered, opaque envelopes. Dr. Houle will 
generate the randomization (using SAS program “PROC PLAN” statement). Participants in both 
groups will continue to track their migraines with their daily REDCap logs for the duration of the 
trial.   
STUDY INTERVENTIONS  
Interventions, Administration, and Duration  
Interventions and Interactions 
 
The MBSR Intervention: The PI has conducted 2 previous RCTS with MBSR and is a trained 
MBSR instructor. The MBSR instructor for this trial (not the PI to avoid bias) has been trained in 
the structured protocol created by Dr. Kabat-Zinn.95 Given the feasibility of our pilot trial, we 
anticipate that this population will have no difficulty engaging in the standardized protocol. The 
participants will meet weekly for 8 weeks for 2.5 hours, plus a “mindfulness retreat day” 
(approximately 6 hours) after the 6th class [9 total classes.] Mindfulness is cultivated through 
meditation, body scan (sequential attention to parts of the body), and mindful movement (bodily 
awareness during gentle stretching, based on hatha yoga). Participants can share their 
mindfulness experiences with others. The instructor also gives information about stress and 
stress relief. Participants are advised to incorporate mindfulness into their daily lives so that 
routine activities (brushing teeth, taking a shower, etc.) become a meditative practice. Each 
participant will be given the same standard guided audio recordings and encouraged to practice 
at home for 30-45 minutes per day, at least 5 additional days per week. Compliance will be 
monitored through class attendance and by daily logs of home practice (using REDCap). Once 
the course is completed, the participants will be advised to continue in their daily practice.   
 
The Control Group: Migraine/Stress Education: The control group will meet for 8 weeks for 
2.5 hours, plus a 1 day learning session. Content will include education about migraine 
pathophysiology, headache triggers, stress, and gentle stretches. The goal of the control group 
is to match the time/attention/expectation of the MBSR group, without providing key MBSR 
active ingredients of mindfulness meditation or yoga. The group will be taught by a health care 
provider trained in headache care.   

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Concomitant Interventions  
Participants may stay on stable dosages of current migraine medications for the duration of the 
trial, but will be excluded from starting any new medication within four weeks of screening visit.  
This makes this study very generalizable to the general population of migraine patients seeking 
treatment, as most are already on some form of pharmacological treatment and will not need to 
stop such treatment to participate in the trial.  Further, it could be dangerous for a participant to 
stop migraine medications as it could exacerbate their underlying headache condition.   
Adherence Assessment  
Adherence to the interventions will be measured by the number of weekly classes/retreat day 
the participants attend; participants will be considered “completers” of the intervention if they 
attend at least 5/9 weekly classes/retreat day.  Participants who are not able to commit to at 
least 6/8 classes, and attend the very first class, from the onset of the study will be advised to 
not participate in the study, so the number of non-completers should be low.    
The survey assessments will be completed using REDCap and study personnel will ensure all 
questions are answered before participants leave each session (See Table 8). Study personnel 
will also be conducting the QST pain assessments so adherence to both pain testing and survey 
assessments will be high.   
Participants will keep daily headache logs and will receive an email via REDCap with the link to 
complete these logs.  If a participant misses capturing a day of the log, study staff will contact 
the participant by phone or email and reinforce the importance of completing the daily log.  
Participants in the MBSR group will also keep track of their assigned home activities with a daily 
log in a similar way. Participants will also be contacted by phone call, letter, or email for 
appointment reminders.  
After 8 weekly classes have concluded, study participants will be incentivized to keep daily 
headache logs as follows: 
1. For each DAY that the participant keeps their headache log on time, their name will be 
entered into a drawing (will have the chance to get their name in the drawing up to 30 
times in a month) 
2. At the end of the month, a name will be drawn and a winner will receive a $50 Amazon 
gift card 
 

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STUDY PROCEDURES  
 
Table 6 - Summary of Schedule of Evaluations – Part 1 – Migraineurs 
Assessment 
Telephone Screen 
Study Visit 
Confirm Eligibility 
X 
X 
Review Study Protocol 
X 
X 
Sign ICF 
 
X 
Allodynia Symptom Checklist 
 
X 
DERS 
 
X 
PCS 
 
X 
GAD-7 
 
X 
PHQ-9 
 
X 
CPAQ 
 
X 
HIT-6 
 
X 
MIDAS – one month 
 
X 
HA management self-efficacy 
 
X 
MSQOL 
 
X 
Mindfulness, FFM 
 
X 
PSS 
 
X 
Herth Hope Index 
 
X 
Life Orientation Test 
 
X 
Social Connectiveness Scale 
 
X 
Flourishing Scale 
 
X 
Brief Resilience Scale 
 
X 
NIH-Promis Measures of Sleep 
Disturbance 
 
X 
NIH-Promis Measures of Global Health 
(first question only) 
 
X 
Pittsburgh Sleep Quality Index 
 
X 
QST Measurements  
 
X 
Pain Threshold Testing 
 
X 
Vitals 
 
X 
QST – Quantitative Sensory Testing 
 
Table 7 - Summary of Schedule of Evaluations – Part 1 – Healthy Volunteers 
 
Assessment 
Telephone Screen 
Study Visit 

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Confirm Eligibility 
X 
X 
Review Study Protocol 
X 
X 
Sign ICF 
 
X 
Allodynia Symptom Checklist 
 
X 
DERS 
 
X 
PCS 
 
X 
GAD-7 
 
X 
PHQ-9 
 
X 
Mindfulness, FFM 
 
X 
PSS 
 
X 
Herth Hope Index 
 
X 
Life Orientation Test 
 
X 
Social Connectiveness Scale 
 
X 
Flourishing Scale 
 
X 
Brief Resilience Scale 
 
X 
NIH-Promis Measures of Sleep 
Disturbance 
 
X 
NIH-Promis Measures of Global Health 
(first question only) 
 
X 
Pittsburgh Sleep Quality Index 
 
X 
QST Measurements 
 
X 
Pain Threshold Testing 
 
X 
Vitals 
 
X 
QST – Quantitative Sensory Testing 
 
Table 8: Summary of Schedule of Evaluations-Part II 
Assessment 
Telephone 
Screen 
Screening/ 
Baseline 
Visit 
Phone Call 
post 4 
week 
baseline 
Headache 
log 
Initial 
F/U 
3mo 
follow-up 
6 mo 
follow-up 
Inclusion/Exclusion Criteria 
X 
X 
 
 
 
 
Enrollment 
 
X 
 
 
 
 
Vitals 
 
X 
 
X 
X 
X 
Teach use of REDCap 
 
X 
 
 
 
 

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Informed Consent Form 
 
X 
 
 
 
 
Randomization 
 
 
X 
 
 
 
Sociodemographic information 
 
X 
 
 
 
 
Neurology Evaluation 
 
X 
 
 
 
 
Headache Log 
 
Begin 
Continue 
Continue 
Continue 
Continue 
QST Heat Pain Assessments 
 
X 
 
X 
X 
X 
INSTRUMENTS 
 
X 
 
X 
X 
X 
Mindfulness-FFM 
 
X 
 
X 
X 
X 
Emotion Regulation-DERS 
 
X 
 
X 
X 
X 
Pain Catastrophizing-PCS 
 
X 
 
X 
X 
X 
Pain Acceptance-CPAQ 
 
X 
 
X 
X 
X 
Headache-related Disability 
-HIT-6 
 
X 
 
X 
X 
X 
Headache-related Disability 
-MIDAS-one month 
 
X 
 
X 
X 
X 
HA Management Self –
Efficacy 
 
X 
 
X 
X 
X 
Quality of Life-MSQOL, V.21 
 
X 
 
X 
X 
X 
Perceived Stress-PSS-10 
 
X 
 
X 
X 
X 
Depression-PHQ-9 
 
X 
 
X 
X 
X 
Anxiety-GAD-7 
 
X 
 
X 
X 
X 
Hope-Herth Hope Index 
(HHI) 
 
X 
 
X 
X 
X 
Optimisim-Life Orientation 
Test-revised (LOT-R) 
 
X 
 
X 
X 
X 
NIH PROMIS Sleep 
Disturbance 
 
X 
 
X 
X 
X 
NIH PROMIS Global Health 
(first question only) 
 
X 
 
X 
X 
X 
Pittsburgh Sleep Quality 
Index 
 
X 
 
X 
X 
X 
Social Connectedness Scale 
– Revised 
 
X 
 
X 
X 
X 
Flourishing Scale 
 
X 
 
X 
X 
X 
Brief Resilience Scale 
 
X 
 
X 
X 
X 
Credibility/Expectation 
Questionnaire 
 
X 
 
After 2nd 
class 
 
 

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FFM-Five 
Factor 
Mindfulness 
Scale 
DERS-
Difficulty in 
Emotion 
Regulation 
PCS-Pain Catastrophizing Scale 
CPAQ-Chronic Pain Acceptance Questionnaire 
HIT-6: Headache Impact Test-6 
MIDAS-Migraine Disability Assessment-one month 
MSQOL-Migraine Specific Quality of Life, version 2.1 
PSS-10-Perceived Stress Scale 10 
PHQ-9: Patient Health-related Questionnaire-depression module 9 
GAD-7: Generalized Anxiety Disorder 7 
 
 
 
 
Working Alliance Inventory 
 
 
After 
second 
class 
X 
 
 
Client Satisfaction Questionnaire 
 
 
 
X 
 
 
Patient Exit Interview-for Patient 
Centered Communication Skills 
 
 
At end of 
each 8 
week class 
X 
 
 
Class Attendance 
 
 
During 8 
week class 
 
 
 
Home Practice 
 
 
Begin with 
1st class 
Continue 
Continue 
Continue 
Qualitative Interview 
 
 
 
X 
 
 
Adverse Events 
 
 
Begin with 
1st class 
Continue 
Continue 
Continue 
Allodynia Symptom Checklist 
 
X 
 
X 
X 
X 

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Description of Evaluations  
 
D- Experimental Session of Quantitative Sensory Testing (QST) Measurements: 
Thermal Probe: MEDOC TSA-II will deliver thermal stimuli with a 16 x 16 mm thermal probe. 
All temperatures will be < 50°C and no stimulus as designed produces tissue damage. We 
have significant experience using this technique and probe with no adverse events (Coghill’s 
lab on > 750 subjects). 
 
Psychophysical Training: To gain experience rating pain, subjects will be familiarized with 
32, 5-second duration stimuli (35 to 49°C) with the Visual Analogue Scale (VAS), a 15 cm 
plastic sliding scale used to quantify pain sensation intensity and degree of 
Telephone Screen:   
A study investigator will contact interested participants for a pre-screening telephone interview.  
At the beginning of the phone call, potential subjects will be informed of the nature and 
sensitivity of the questions, asked whether this is an appropriate time for them to answer these 
questions, and told how long the phone call is expected to take.  Participants will be offered the 
option of completing the pre-screening in person, if they wish and if it is feasible.  The pre-
screening telephone interview will be performed to explain the protocol, determine eligibility, 
discuss informed consent, and answer questions.  If eligible, they will then be offered 
participation.  Those interested and eligible will be either immediately scheduled for a screening 
visit or will be called in the future to set it up.  A letter will then be sent to them, with the consent 
form attached for review ahead of time if they would like, in advance of their study visit. 
 
Baseline Visit: 
The study staff will: 
 
A-Consent Participants-Consenting procedures: 
We will obtain consent before the experiment begins. At the onset of the study visit, 
participants will be provided informed consent by the PI or a qualified study team member. 
The consenting process will occur in a private clinic room. Subjects will be given time to ask 
questions and can discuss with family members.  The consent form states the title and 
purpose of the study, an estimate of how many people may enroll, the duration of 
participation, the procedures that will be followed, any reasonably foreseeable risks or 
discomforts, and benefits to the participants or others that may be expected from the 
research.  Information is provided about the disclosure and confidentiality of protected 
health information they will provide, that there is no cost to participants in the study, who 
sponsors the study, what happens if they experience an injury or illness as a result of 
participating, and whom to call if they have a question or problem. Participants will be 
informed of payment ($80 for completion of the study; $10 after the screening visit; $15 after 
the initial follow-up visit; $20 after the 3 month follow-up visit; and $35 after the 6 month 
follow-up visit). The telephone number of the Chairman of the Institutional Review Board will 
also be included for questions regarding rights as research subjects. The consent form will 
be signed and dated by the participant and by the person obtaining consent.  We have 
obtained IRB approval for the study and the informed consent documents (Wake Forest IRB 
protocol # IRB00027845). 
 
B-Neurology evaluation to confirm migraine diagnosis with history/neurological exam.   
Neurology evaluation will include vital signs, detailed headache and medical history, 
neurological exam (will include Structured Diagnostic Interview for Headache), and general 
physical exam.  If participants have a headache at the time of the study visit, they will be 
rescheduled for a time when headache-free.   
 
C-Complete baseline sociodemographic information and complete full set of 
instruments (See Schedule of assessments for full listing of all instruments) 
 

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unpleasantness.37 The VAS is an ideal pain measurement scale because of its ratio scale 
properties combined with its ease of administration and scoring.38 The minimum rating is “no 
pain sensation” or “not all unpleasant” whereas the maximum is designated as “most intense 
imaginable” or “most unpleasant imaginable.” The training will be conducted on the left arm, 
a location away from increased sensitivity/allodynia of head/neck regions often seen in 
patients with migraines.   
 
Pain Threshold Assessment:  The temperature of the probe will begin at 32°C and will 
increase at a rate of 0.5°C per second. The subject will be instructed to verbally respond 
when he or she first detects a sensation of pain. The thermode will return to baseline once 
the button is pressed. This will be performed up to four times, and the heat pain threshold 
will be determined as the average of the temperatures at which the stimulus was first 
perceived as painful (Yarnitsky and Sprecher, 1994). Stimulus temperatures employed for 
pain threshold testing will not exceed 50°C. This will be conducted on the right arm. 
 
Experimental Session: We will administer the noxious thermal stimulation on the right calf  
by starting at 35°C and increasing with a 6°C rise/fall rate with a 5 second plateau up to the 
randomly administered temperatures of 43, 45, 47, and 49°C. Each temperature will be 
repeated x 3 and delivered pseudorandomly. To minimize sensitization, habituation, and 
hyperalgesia, all trials will be separated by 30 seconds and systematically distributed over 
the calf to minimize repetitive stimulation of the same skin site.1,37,39  Perception of intensity 
and unpleasantness will be measured with the VAS scale after each temperature. Each 
series will be repeated twice. Dr. Wells has been trained in the performance and analysis of 
QST measurements.  
 
The specified arm/leg positioning of the probe may be adjusted if needed. 
 
E-Headache Logs-Participants will be taught by study staff how to capture daily migraine 
information using REDCap electronic data capture tools (or iPod touches for those without 
internet access).  Headache logs will capture migraine day, duration, severity (pain intensity 
and pain unpleasantness), medications used for treatment, associated symptoms (nausea, 
vomiting, photophobia, phonophobia, osmophobia) 
 
Randomization: 
After the baseline evaluation, participants will track migraines x 4 weeks to 1) confirm 
diagnosis; 2) confirm ability to log daily; and 3) use as the 4 week “pre-trial” baseline 
migraine data. Once 4-week migraine logs are reviewed by study staff to ensure eligibility, 
participants will be randomized 1:1 to either MBSR or the control group, stratified by 
migraine frequency (low frequency of 4-9 headaches/month or high frequency of 10-20 
headaches/month).. Treatment assignments will be generated by a permuted blocks method 
with randomly varying block size and sealed in numbered, opaque envelopes. Dr. Houle will 
generate the randomization (using SAS program “PROC PLAN” statement). Participants in 
both groups will continue to track their migraines with their daily REDCap logs for the duration 
of the trial. The PI will be blinded to the randomization groups. 
 
Selection Bias, Blinding and Expectations: Recruitment materials and consents will state 
we are studying “better ways to manage migraines” without describing meditation or yoga. 
This approach will serve three purposes: 1) participants will be blinded to the active 
intervention; 2) we will avoid having participants who are only interested in MBSR, which 
could cause selection bias and increase the risk of control group dropouts; 3) this will 
minimize differences in expectations (which we will also measure) based on group 
assignment.      
 
Expectations will be measured using Credibility/Expectancy Questionnaire96 at the baseline 
visit AND after the 2nd class session.     
 

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Therapeutic Alliance:  The two interventions require instructors with different expertise and 
cannot be the same person. However, the quality of the therapeutic relationship between 
participant and instructor will be measured after the interventions (at the initial follow-up) 
using the 12 item Working Alliance Inventory. 
 
Treatment Fidelity: In addition to having the same instructor for each group lead all 
cohorts, we will implement a detailed treatment fidelity plan to monitor and ensure that the 
design, delivery, and receipt of both interventions are completed as intended (see Table 
7).97,98 We will also assess satisfaction with the programs with the Client Satisfaction 
Questionnaire99 at the initial follow-up.   
 
 
 
 
Table 7: Assessment of Treatment Fidelity  
Aspect of Treatment 
Fidelity  
Way to Ensure Fidelity is 
Accomplished 
Further details 
Study Design 
Both intervention and control groups will 
receive the same “dose” of 8 weekly 2.5 
hour classes, plus one “retreat” day, and 
may have daily homework of 30-45 
minutes/day 
 
 
Both instructors will follow detailed 
manuals for conducting their intervention 
MBSR intervention will be 
conducted according to 
standard MBSR protocol 
Provider Training 
MBSR instructor is certified in teaching 
MBSR, has taught over 25 MBSR 
courses 
Headache education provider is 
a neurologist with headache 
expertise 
Treatment Delivery 
Both instructors will be audiotaped during 
their sessions and 10% of randomly 
selected audiotapes will be reviewed to 
confirm treatment delivered as intended 
using checklists of required elements for 
each intervention and with evaluations of 
instructor’s communication style; 
feedback will be provided if any 
deviations from expectations 
 
 
Both instructors will have a standard 
expected check-list of both critical and 
minimal intervention components for 
each session’s goals/requirements and 
will complete it at the end of each 
session  
 
 
Participants will complete Patient Exit 
Interview to assess Patient Centered 
Communication Styles100 of each group 
leader at the end of each session; 
participants will complete and place in 
sealed envelope so participant 
confidentiality maintained and instructor 
will not have access 
The 2 instructors have been 
chosen specifically with similar 
interpersonal skills and levels of 
compassion with patient 
interactions 
 
Qualitative Interviews will further assess 
participants’ perceptions of instructors’ 
warmth and credibility 
 
Treatment Receipt 
Class attendance will be monitored 
 

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Enactment of Treatment 
skills 
Participants will keep a daily log to track 
home activities if assigned 
 
 
Qualitative interviews will also capture 
how individuals used/applied skills in 
their daily lives 
 
  
FOLLOW-UP VISITS 
Follow-up visits will occur immediately after the 8 week class is over, 3 months later and 6 
months later.  At each follow-up visit, participants will complete the entire instrument 
assessment and the QST measurements. In addition, at the first follow-up visit, participants will 
complete a qualitative interview. 
 
Qualitative Interviews: At the initial follow-up, a 30-minute semi-structured interview will be 
conducted with participants to further explore areas not captured in our standardized 
quantitative measures. This will be especially important in capturing measures of treatment 
fidelity not already captured, especially in capturing patient/instructor interactions and 
enactment of treatment skills.   
 
 
 
 
Reporting Procedures 
 
Plans for ensuring necessary medical or professional intervention in the event of 
adverse effects to the subjects.  Dr. Wells is a trained clinician and will oversee the 
interventions. If a medical emergency arises the appropriate steps will be taken to contact 
emergency services. At each study visit, the PHQ-9 survey will be scored immediately after 
completion by the participant. If the participant’s responses suggest severe clinical depression, 
Dr. Wells will recommend that the participant see their primary care physician for treatment. If 
the participant’s responses suggest active suicidal ideation, he or she will be sent directly to the 
emergency department.  
 
We will promptly report any unanticipated problems, serious and unexpected adverse events, 
deviations or protocol changes to the IRB and Data Safety and Monitoring Board (See Data 
Safety and Monitoring Board for more details). 
 
Serious adverse events (SAEs) that are unanticipated, serious, and possibly related to the study 
intervention will be reported to the I-DSMB, Wake Forest School of Medicine IRB, and NCCIH in 
accordance with requirements. 
 
Unexpected fatal or life-threatening AEs related to the intervention will be reported to the NCCIH 
Program Officer within 7 days. Other serious and unexpected AEs related to the intervention will 
be reported to the NCCIH Program Official within 15 days. 
 
Anticipated or unrelated SAEs will be handled in a less urgent manner but will be reported to the 
I-DSMB, Wake Forest School of Medicine IRB, NCCIH, and other oversight organizations in 
accordance with their requirements. In the annual AE summary, the I-DSMB Report will state 
that they have reviewed all AE reports. 
 
The WFSM Institutional Data & Safety Monitoring Board (I-DSMB) will monitor the study for 
purposes of evaluating participant safety and study integrity. The I-DSMB is a Dean-appointed, 
multi-disciplinary, standing committee that is available to provide independent oversight for 
human research studies conducted by WFSM or by WFSM-affiliated faculty investigators. The 
board will review the progress of and safety for the study as described above in Part I.   The 
DSMB will meet to review safety data at least once annually while the study has active 
participants, even if the prespecified review targets, as specified above, have not been met. 

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There will be no fee for the independent monitoring of the study. All protocol deviations and 
adverse events will be promptly reported to the I-DSMB as well the IRB. See DSMB plan for 
more details. See Table 3 above for further details of reporting. 
 
Risks to subjects are reasonable in relation to the anticipated benefits to subjects and 
others.   
The risks in participating in this study are minimal and the benefits can be significant to those 
who experience migraines. We will learn how Mindfulness based stress reduction techniques 
can assist with migraine pain. This work can be instrumental in employing safe non-
pharmacological interventions for migraine pain which may be particularly beneficial as the 
MBSR technique can be performed concurrently with medications and have few side effects and 
may play a role in reducing stress. 
 
Potential Risks 
Potential physical, psychological, social, legal or other risks, their likelihood of 
occurring, seriousness to participants.  
 
Experimental Heat Pain Assessments:  The quantitative sensory testing may cause 
brief pain, but all temperatures will be < 50°C and no stimulus as designed produces 
tissue damage.. The thermal probe used for this experiment, MEDOC TSA-II, will deliver 
thermal stimuli with a 16 x 16 mm thermal probe. 
 
The subject can easily pull away from the device if the feeling is not tolerable. Dr. 
Coghill’s laboratory staff are experts in conducting the heat-pain intervention and the 
temperature of the thermal heat probe will be monitored at all times. His lab has 
conducted this procedure on over 750 participants and no serious adverse events have 
been associated with this device. 
 
Mindfulness Body Stress Reduction intervention/Headache Education Control 
Group: A risk to taking part in this study is the likelihood of receiving an intervention 
(that requires time and energy) that may not be effective in helping to treat migraines.  
The classes or other study-related procedures may cause some, all, or none of the side 
effects listed below. 
Most Likely 
Gentle stretching can cause muscle soreness if muscles have not been exercised in a 
long time.  Sitting for extended periods of time can be uncomfortable.  Chairs will be 
provided for comfort, and participants will be allowed to move as needed to relieve any 
discomfort.   
Less Likely 
With any activity, there is always a risk of injury.  The instructor will advise the 
participants to avoid any posture that causes discomfort or pain.  The instructor will be 
attuned to watching for any problems during each session. 
Rare 
There have been rare case reports of meditation or yoga causing a brief limited episode 
of psychiatric illness. However, most of these case reports are in individuals with a prior 
history of unstable psychiatric illness.  There are no known reports of this occurring in 
anyone in an MBSR class. Having a history of unstable psychiatric illness is an exclusion 
criteria for participating in this project so therefore we have in place an extra precaution 
to not encounter this risk. 
 
Description of alternative treatments and procedures.  The alternative is to not participate in 
the study or to refer to the personal physician for standard treatment. 

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STATISTICAL CONSIDERATIONS  
General Design Issues  
To examine the hypotheses, we will again rely on mixed effects hierarchical regression models 
with a distribution and link function appropriate to the outcome (e.g., binomial distribution and 
logit link for daily migraine probability). These models will allow us to fully utilize all of the 
information (i.e., rather than simply calculating change scores) by conceptualizing each diary 
entry as nested within a diary phase (baseline 4 weeks prior to randomization, 8 weeks of 
treatment, and 3 and 6 months of follow-up), within a person (random effects), who is nested 
within a treatment group. Missing data will be scrutinized and we will utilize sensitivity analyses 
and/or multiple imputation as required.  The models will be conducted as described below:  
Hypothesis 2a:  MBSR will decrease the primary outcome of migraine frequency compared to 
an education control group; 
Hypothesis 2b: MBSR will differentially affect the secondary outcome of the affective component 
(pain unpleasantness) of experimental heat pain compared to the education control group. 
Hypothesis 2c: MBSR will improve the secondary outcomes of mindfulness, emotion regulation, 
pain acceptance, pain catastrophizing, and headache-related disability compared to an 
education control group.   
Hypothesis 3A:  High levels of baseline pain catastrophizing and emotional reactivity scores and 
high baseline levels of pain unpleasantness for experimental pain will predict the primary 
outcome response (migraine frequency) to MBSR.   
Hypothesis 3B: Changes in mindfulness after MBSR will be directly associated with 
improvements in migraine frequency.   
Sample Size and Randomization 
Sample Size Calculation: For hypothesis 2a, using effect sizes from our pilot trial,58 and by 
analyzing the data with our mixed effects hierarchical regression models, 44 participants/group 
(n=88) will provide >90% power with α=0.05 to detect a difference of 1.3 migraine days/month 
over the course of the trial (used PASS design) (Hypothesis 2a). Hypothesis 2b has a similar 
power function as Part I of this study. For hypothesis 3: since hypothesis 3b is the most difficult 
to evaluate, this RCT is powered on this hypothesis. This calculation assumes a multivariable 
model examining linear changes with the four predictors (plus intercept and slope). A sample 
size of 88 participants will give us 80% power with effects as small as R2 ≥ 6% in the variance of 
the slopes; smaller predictors are unlikely to be clinically significant.101 
 
Randomization: Once 4-week migraine logs are reviewed by study staff to ensure eligibility, 
participants will be randomized 1:1 to either MBSR or the education control group, stratified by 
migraine frequency (low frequency of 4-9 headaches/month or high frequency of 10-20 
headaches/month).. Treatment assignments will be generated by a permuted blocks method 
with randomly varying block size and sealed in numbered, opaque envelopes. Dr. Houle will 
generate the randomization (using the statistical SAS program “PROC PLAN” statement) and 
deliver the envelopes to the PI. Participants in both groups will continue to track their migraines 
with their daily REDCap logs for the duration of the trial.   
Definition of Populations 
As done in prior behavioral headache research,69 all participants who attend at least ONE class 
will be included in the intention-to-treat analyses.  This is a modified “intent to treat” analysis that 
ensures exposure to the independent variable and is used and felt to be very important by 
behavioral scientists. 
Outcomes  
Our primary outcome will be change in frequency of migraine days, defined as a calendar day 
(00:00 to 23:59)102 when the patient reports 4 or more continuous hours of a moderate to severe 
headache (rating of 6-10 on 0-10 VAS pain intensity scale) and/or they treated a headache with 
abortive medication. Participants will track their headaches daily with REDCap logs to 

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demonstrate frequency, severity (both pain intensity and pain unpleasantness, as trained with 
QST), medications, and associated migraine symptoms (e.g., photophobia, phonophobia, 
nausea, vomiting). iPod Touch devices with Pendragon software will be available to those 
without internet access. 
 
Secondary outcomes include changes in migraine severity (measured by pain intensity and 
unpleasantness on 0-10 VAS scale), migraine duration (hrs), frequency of headache days, 
headache duration, headache severity (measured by pain intensity and unpleasantness on 0-10 
VAS scale), experimental heat pain intensity and unpleasantness (QST measurements), and 
changes in scores on validated measures  of mindfulness, pain acceptance, pain 
catastrophizing, emotional reactivity, and headache-related disability compared to an education 
control group; determine factors that predict MBSR response on migraine pain.  A headache 
day is defined as any day when a participant reports the presence of a headache.  
 
We will also characterize participants before/after the intervention using measures of hope, 
optimism, quality of life, depression, anxiety, perceived stress, self-efficacy, sleep, fatigue, pain 
interference, satisfaction with participation in social roles, allodynia, and global health.   
 
All the secondary outcomes and additional measures will be assessed with these standardized, 
reliable, well-validated instruments: Five-Facet Mindfulness Questionnaire (mindfulness),57,103 
DERS (emotion regulation),3,104 PCS (pain catastrophizing),2,36 Chronic Pain Acceptance 
Questionnaire (pain acceptance),105 Herth Hope Index (hope),106 Life Orientation Test-Revised 
(optimism),107  Headache Impact Test-6 (HIT-6) (headache related disability),108-110 Migraine 
Disability Assessment (MIDAS)-one month (headache related disability),111,112 Patient Health 
Questionnaire-depression module, PHQ-9 (depression),34 Generalized Anxiety Disorder-7, 
GAD-7 (anxiety),35  Headache Management Self-Efficacy Scale (self-efficacy),113 Migraine 
Specific Quality of Life Questionnaire, version 2.1 (MSQv2.1) (quality of life),114,115 the Perceived 
Stress Scale 10, PSS (perceived stress), 116 the Brief Resilience Scale, the Resilience Scale for 
Adults, the Flourishing Scale, the Social Connectedness Scale-Revised (SCS-R), the 
PittsburghSleep Quality Index, the Allodynia Symptom Checklist (ASC-12), and well-validated 
NIH Patient Reported Outcomes Measurement Information System (PROMIS) measures of 
sleep, fatigue, pain interference, satisfaction with participation in social roles, and global health.  
Changes from baseline to initial follow-up will be primary outcomes; secondary outcomes will 
include changes from baseline to follow-ups at 3 and 6 months. 
 
 
 
Additional Information Collected 
Sociodemographic and clinical information will be collected at the screening visit.  
 
Expectations for improvement: Expectations can impact results.39,117 At baseline and after the 
second session, participants will rate their expectations using the Credibility/Expectancy 
Questionnaire.96  
 
Class Attendance and Home Practice: Participants in both groups will track their home activities 
up to the 6-month follow-up visit via REDCap logs and the instructors will track patient class 
attendance.  
 
Qualitative Interviews: At the initial follow-up, a 30-minute semi-structured interview will be 
conducted with participants to further explore areas not captured in our standardized 
quantitative measures.  
Data Analyses  
Analysis 2a: The probability that an individual experiences a migraine on any given day will be 
examined as a function of group (MBSR vs. control) and treatment phase. A statistically 
significant group x phase interaction will be interpreted as evidence that treatment differentially 

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impacted the daily probability of migraine. This effect size will be indexed by converting the daily 
probability to headache counts as recommended for clinical trials in headache. 118  If necessary 
we will model change using polynomial trajectories (i.e., growth curves) to better fit the time-
course of treatment. 
Analysis 2b: To examine this hypothesis, we will conduct an ANCOVA with pain unpleasantness 
at post-treatment as the dependent variable, group as the independent variable, and pain 
unpleasantness at pre-treatment as the covariate. 
Analysis 2c: This analysis is identical to 2b, with the appropriate outcomes. 
Analysis 3a: Baseline levels of pain catastrophizing and emotional reactivity will be used as 
predictors in the multilevel models predicting the trajectory of migraine attacks over the course 
of treatment.   
Analyses 3b: This analysis is similar to 3a, except that changes in mindfulness (i.e., change 
scores from pre-treatment to post-treatment) will be used as predictor of migraine trajectory. 
DATA COLLECTION AND QUALITY ASSURANCE 
Data Collection Forms  
Information will be collected from REDCap daily headache logs for appropriate diagnosis 
of migraines during an initial 4 week period prior to randomization and participants will 
continue to track daily headaches for the duration of the trial. Ipod touches with 
Pendragon software will be available to those without internet access and unable to use 
REDCap from home.  Experimental heat measurements will be conducted at baseline and 
at each of the 3 follow-up evaluations. Participants will also complete standardized 
questionnaires using REDCap at baseline and at each of the 3 follow-up evaluations with 
an option to complete these questionnaires at home prior to the visit. In addition, a 30 
minute qualitative interview will be conducted at the first follow-up visit to evaluate the 
participants’ experience with the interventions. Each interview will be audiotaped. Socio-
demographic and clinical information will also be collected at the screening visit.  
Description of data that will be recorded on human subjects.  Each 30 minute 
qualitative interview of the migraine and control subjects will be audiotaped and then 
transcribed. Participants will be photographed one of the study visits. These photos will 
be stored on the study’s secure Ishare.  Each subject will have provided informed 
consent to perform this.  
Description of linkages to subjects and who will have access to subject identities.  
WFSM investigators and study staff will take measures to ensure the privacy and 
confidentiality of all study subjects. All participants will be assigned a study ID (unique 
ID) that will be used to link participant records and identify participants within the 
database.  Only study investigators and the study team members will have access to the 
identity of participants.   
Information about how specimens, records and data are collected; data collected 
specifically for research.  All data are collected according to IRB approved study 
protocols specifically for research purposes.  Specimens, records and data will be 
collected by study investigators, staff and physicians upon enrollment of the patients.     
Quality Assurance  
Protection Against Risk 
Description of procedures for protecting against or minimizing potential risks, including 
risks to confidentiality, and assessment of likely effectiveness.  All data collected will be 
completely confidential. Only investigators and their staff directly involved in this study will have 
access to the data.  Records and forms will be kept in a locked file cabinet when not in use.  No 
names will be stored on computer files for data analysis; no individuals will be identified in the 
results of this study.  Access to computer-stored information will require knowledge of the data 
format, filename and password.  Dr. Wells will use the results of this study for research only and 

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not include the results in a medical record.  Any data that may be published in scientific journals 
will not reveal the subject’s identity. 
 
Plans for ensuring necessary medical or professional intervention in the event of 
adverse effects to the subjects.  Dr. Wells is a trained clinician and will oversee the 
interventions. If a medical emergency arises the appropriate steps will be taken to contact 
emergency services.  
Institutional Review Board (IRB) Review  
This protocol and the informed consent document have been approved by Wake Forest’s IRB 
(Wake Forest IRB protocol # IRB00027845). 
PUBLICATION OF RESEARCH FINDINGS  
We plan to publish our findings in top-tier scientific, peer-reviewed journals.  
 
 
REFERENCES  
 
1. 
Starr CJ, Houle TT, Coghill RC. Psychological and sensory predictors of experimental 
thermal pain: a multifactorial model. The journal of pain : official journal of the 
American Pain Society. Dec 2010;11(12):1394-1402. 
2. 
Sullivan MJL, Bishop SR, Pivik J. The Pain Catastrophizing Scale: Development and 
Validation. Psychological Assessment. 1995;7(4):524-532. 
3. 
Kokonyei G, Urban R, Reinhardt M, Jozan A, Demetrovics Z. The Difficulties in 
Emotion Regulation Scale: Factor Structure in Chronic Pain Patients. Journal of clinical 
psychology. Sep 3 2013. 
4. 
Hu XH, Markson LE, Lipton RB, Stewart WF, Berger ML. Burden of migraine in the 
United States: disability and economic costs. Archives of internal medicine. Apr 26 
1999;159(8):813-818. 
5. 
Lipton RB, Bigal ME, Diamond M, Freitag F, Reed ML, Stewart WF, Group AA. 
Migraine prevalence, disease burden, and the need for preventive therapy. Neurology. Jan 
30 2007;68(5):343-349. 
6. 
Lipton RB, Stewart WF, Diamond S, Diamond ML, Reed M. Prevalence and burden of 
migraine in the United States: data from the American Migraine Study II. Headache. Jul-
Aug 2001;41(7):646-657. 
7. 
Leung L. Pain catastrophizing: an updated review. Indian J. Psychol. Med. Jul 
2012;34(3):204-217. 
8. 
Geisser ME, Robinson ME, Keefe FJ, Weiner ML. Catastrophizing, depression and the 
sensory, affective and evaluative aspects of chronic pain. Pain. Oct 1994;59(1):79-83. 
9. 
Gracely RH, Geisser ME, Giesecke T, Grant MA, Petzke F, Williams DA, Clauw DJ. 
Pain catastrophizing and neural responses to pain among persons with fibromyalgia. 
Brain. Apr 2004;127(Pt 4):835-843. 
10. 
Michael ES, Burns JW. Catastrophizing and pain sensitivity among chronic pain patients: 
moderating effects of sensory and affect focus. Ann. Behav. Med. Jun 2004;27(3):185-
194. 
11. 
Seminowicz DA, Davis KD. Cortical responses to pain in healthy individuals depends on 
pain catastrophizing. Pain. Feb 2006;120(3):297-306. 
12. 
Lackner JM, Quigley BM. Pain catastrophizing mediates the relationship between worry 
and pain suffering in patients with irritable bowel syndrome. Behav. Res. Ther. Jul 
2005;43(7):943-957. 

Protocol Template, Version 1.0 
32 of 37 
13. 
Quartana PJ, Campbell CM, Edwards RR. Pain catastrophizing: a critical review. Expert 
Rev. Neurother. May 2009;9(5):745-758. 
14. 
Sullivan MJ, Lynch ME, Clark AJ. Dimensions of catastrophic thinking associated with 
pain experience and disability in patients with neuropathic pain conditions. Pain. Feb 
2005;113(3):310-315. 
15. 
Sullivan MJ, Stanish W, Waite H, Sullivan M, Tripp DA. Catastrophizing, pain, and 
disability in patients with soft-tissue injuries. Pain. Sep 1998;77(3):253-260. 
16. 
Peters ML, Vlaeyen JW, Weber WE. The joint contribution of physical pathology, pain-
related fear and catastrophizing to chronic back pain disability. Pain. Jan 2005;113(1-
2):45-50. 
17. 
Edwards RR, Bingham CO, 3rd, Bathon J, Haythornthwaite JA. Catastrophizing and pain 
in arthritis, fibromyalgia, and other rheumatic diseases. Arthritis Rheum. Apr 15 
2006;55(2):325-332. 
18. 
Buenaver LF, Edwards RR, Smith MT, Gramling SE, Haythornthwaite JA. 
Catastrophizing and pain-coping in young adults: associations with depressive symptoms 
and headache pain. J. Pain. Apr 2008;9(4):311-319. 
19. 
Drahovzal DN, Stewart SH, Sullivan MJ. Tendency to catastrophize somatic sensations: 
pain catastrophizing and anxiety sensitivity in predicting headache. Cogn. Behav. Ther. 
2006;35(4):226-235. 
20. 
Holroyd KA, Drew JB, Cottrell CK, Romanek KM, Heh V. Impaired functioning and 
quality of life in severe migraine: the role of catastrophizing and associated symptoms. 
Cephalalgia. Oct 2007;27(10):1156-1165. 
21. 
Kroner-Herwig B, Jakle C, Frettloh J, Peters K, Seemann H, Franz C, Basler HD. 
Predicting subjective disability in chronic pain patients. Int. J. Behav. Med. 1996;3(1):30-
41. 
22. 
Buse DC, Silberstein SD, Manack AN, Papapetropoulos S, Lipton RB. Psychiatric 
comorbidities of episodic and chronic migraine. Journal of neurology. Aug 
2013;260(8):1960-1969. 
23. 
Smitherman TA, Davis RE, Walters AB, Young J, Houle TT. Anxiety sensitivity and 
headache: Diagnostic differences, impact, and relations with perceived headache triggers. 
Cephalalgia. Oct 28 2014. 
24. 
Smitherman TA, Maizels M, Penzien DB. Headache chronification: screening and 
behavioral management of comorbid depressive and anxiety disorders. Headache. Jan 
2008;48(1):45-50. 
25. 
Ashina S, Serrano D, Lipton RB, Maizels M, Manack AN, Turkel CC, Reed ML, Buse 
DC. Depression and risk of transformation of episodic to chronic migraine. J Headache 
Pain. Nov 2012;13(8):615-624. 
26. 
Schwedt TJ, Krauss MJ, Frey K, Gereau RWt. Episodic and chronic migraineurs are 
hypersensitive to thermal stimuli between migraine attacks. Cephalalgia : an 
international journal of headache. Jan 2011;31(1):6-12. 
27. 
Nahman-Averbuch H, Granovsky Y, Coghill RC, Yarnitsky D, Sprecher E, Weissman-
Fogel I. Waning of "Conditioned Pain Modulation": A Novel Expression of Subtle 
Pronociception in Migraine. Headache. Apr 17 2013. 
28. 
Stankewitz A, Schulz E, May A. Neuronal correlates of impaired habituation in response 
to repeated trigemino-nociceptive but not to olfactory input in migraineurs: an fMRI 
study. Cephalalgia. Mar 2013;33(4):256-265. 
29. 
Lev R, Granovsky Y, Yarnitsky D. Enhanced pain expectation in migraine: EEG-based 
evidence for impaired prefrontal function. Headache. Jul-Aug 2013;53(7):1054-1070. 
30. 
Schwedt TJ, Zuniga L, Chong CD. Low heat pain thresholds in migraineurs between 
attacks. Cephalalgia : an international journal of headache. Sep 22 2014. 
31. 
Kitaj MB, Klink M. Pain thresholds in daily transformed migraine versus episodic 
migraine headache patients. Headache. Sep 2005;45(8):992-998. 

Protocol Template, Version 1.0 
33 of 37 
32. 
Hassinger HJ, Semenchuk EM, O'Brien WH. Appraisal and coping responses to pain and 
stress in migraine headache sufferers. Journal of behavioral medicine. Aug 
1999;22(4):327-340. 
33. 
Price DD, Harkins SW, Baker C. Sensory-affective relationships among different types of 
clinical and experimental pain. Pain. Mar 1987;28(3):297-307. 
34. 
Kroenke K, Spitzer RL, Williams JB. The PHQ-9: validity of a brief depression severity 
measure. Journal of general internal medicine. Sep 2001;16(9):606-613. 
35. 
Spitzer RL, Kroenke K, Williams JB, Lowe B. A brief measure for assessing generalized 
anxiety disorder: the GAD-7. Archives of internal medicine. May 22 2006;166(10):1092-
1097. 
36. 
Osman A, Barrios FX, Kopper BA, Hauptmann W, Jones J, O'Neill E. Factor structure, 
reliability, and validity of the Pain Catastrophizing Scale. Journal of behavioral 
medicine. Dec 1997;20(6):589-605. 
37. 
Rosier EM, Iadarola MJ, Coghill RC. Reproducibility of pain measurement and pain 
perception. Pain. Jul 2002;98(1-2):205-216. 
38. 
Price DD, Bush FM, Long S, Harkins SW. A comparison of pain measurement 
characteristics of mechanical visual analogue and simple numerical rating scales. Pain. 
Feb 1994;56(2):217-226. 
39. 
Koyama T, McHaffie JG, Laurienti PJ, Coghill RC. The subjective experience of pain: 
where expectations become reality. Proceedings of the National Academy of Sciences of 
the United States of America. Sep 6 2005;102(36):12950-12955. 
40. 
Vickers AJ. How many repeated measures in repeated measures designs? Statistical 
issues for comparative trials. BMC medical research methodology. Oct 27 2003;3:22. 
41. 
Harris PA, Taylor R, Thielke R, Payne J, Gonzalez N, Conde JG. Research electronic 
data capture (REDCap)--a metadata-driven methodology and workflow process for 
providing translational research informatics support. Journal of biomedical informatics. 
Apr 2009;42(2):377-381. 
42. 
Grossman P, Niemann L, Schmidt S, Walach H. Mindfulness-based stress reduction and 
health benefits. A meta-analysis. J. Psychosom. Res. Jul 2004;57(1):35-43. 
43. 
Rosenzweig S, Greeson JM, Reibel DK, Green JS, Jasser SA, Beasley D. Mindfulness-
based stress reduction for chronic pain conditions: variation in treatment outcomes and 
role of home meditation practice. Journal of psychosomatic research. Jan 2010;68(1):29-
36. 
44. 
Chiesa A, Serretti A. Mindfulness-based interventions for chronic pain: a systematic 
review of the evidence. J. Altern. Complement. Med. Jan 2011;17(1):83-93. 
45. 
Miller JJ, Fletcher K, Kabat-Zinn J. Three-year follow-up and clinical implications of a 
mindfulness meditation-based stress reduction intervention in the treatment of anxiety 
disorders. Gen. Hosp. Psychiatry. May 1995;17(3):192-200. 
46. 
Kabat-Zinn J. An outpatient program in behavioral medicine for chronic pain patients 
based on the practice of mindfulness meditation: theoretical considerations and 
preliminary results. General hospital psychiatry. Apr 1982;4(1):33-47. 
47. 
Reiner K, Tibi L, Lipsitz JD. Do mindfulness-based interventions reduce pain intensity? 
A critical review of the literature. Pain Med. Feb 2013;14(2):230-242. 
48. 
Morone NE, Greco CM, Weiner DK. Mindfulness meditation for the treatment of chronic 
low back pain in older adults: a randomized controlled pilot study. Pain. Feb 
2008;134(3):310-319. 
49. 
Kabat-Zinn J, Lipworth L, Burney R. The clinical use of mindfulness meditation for the 
self-regulation of chronic pain. J Behav Med. Jun 1985;8(2):163-190. 
50. 
Lutz A, McFarlin DR, Perlman DM, Salomons TV, Davidson RJ. Altered anterior insula 
activation during anticipation and experience of painful stimuli in expert meditators. 
Neuroimage. Jan 1 2013;64:538-546. 

Protocol Template, Version 1.0 
34 of 37 
51. 
Brown CA, Jones AK. Meditation experience predicts less negative appraisal of pain: 
electrophysiological evidence for the involvement of anticipatory neural responses. Pain. 
Sep 2010;150(3):428-438. 
52. 
Grant JA, Courtemanche J, Duerden EG, Duncan GH, Rainville P. Cortical thickness and 
pain sensitivity in zen meditators. Emotion. Feb 2010;10(1):43-53. 
53. 
Grant JA, Courtemanche J, Rainville P. A non-elaborative mental stance and decoupling 
of executive and pain-related cortices predicts low pain sensitivity in Zen meditators. 
Pain. Jan 2011;152(1):150-156. 
54. 
Grant JA, Rainville P. Pain sensitivity and analgesic effects of mindful states in Zen 
meditators: a cross-sectional study. Psychosom. Med. Jan 2009;71(1):106-114. 
55. 
Zeidan F, Martucci KT, Kraft RA, Gordon NS, McHaffie JG, Coghill RC. Brain 
mechanisms supporting the modulation of pain by mindfulness meditation. J. Neurosci. 
Apr 6 2011;31(14):5540-5548. 
56. 
Gard T, Holzel BK, Sack AT, Hempel H, Lazar SW, Vaitl D, Ott U. Pain attenuation 
through mindfulness is associated with decreased cognitive control and increased sensory 
processing in the brain. Cereb. Cortex. Nov 2012;22(11):2692-2702. 
57. 
Baer RA, Smith GT, Lykins E, Button D, Krietemeyer J, Sauer S, Walsh E, Duggan D, 
Williams JM. Construct validity of the five facet mindfulness questionnaire in meditating 
and nonmeditating samples. Assessment. Sep 2008;15(3):329-342. 
58. 
Wells RE, Burch R, Paulsen RH, Wayne PM, Houle TT, Loder E. Meditation for 
migraines: a pilot randomized controlled trial. Headache. Oct 2014;54(9):1484-1495. 
59. 
Hoge EA, Bui E, Marques L, Metcalf CA, Morris LK, Robinaugh DJ, Worthington JJ, 
Pollack MH, Simon NM. Randomized controlled trial of mindfulness meditation for 
generalized anxiety disorder: effects on anxiety and stress reactivity. J. Clin. Psychiatry. 
Aug 2013;74(8):786-792. 
60. 
Jain S, Shapiro SL, Swanick S, Roesch SC, Mills PJ, Bell I, Schwartz GE. A randomized 
controlled trial of mindfulness meditation versus relaxation training: effects on distress, 
positive states of mind, rumination, and distraction. Ann. Behav. Med. Feb 
2007;33(1):11-21. 
61. 
Creswell JD, Pacilio LE, Lindsay EK, Brown KW. Brief mindfulness meditation training 
alters psychological and neuroendocrine responses to social evaluative stress. 
Psychoneuroendocrinology. Jun 2014;44:1-12. 
62. 
Garland EL, Gaylord SA, Palsson O, Faurot K, Douglas Mann J, Whitehead WE. 
Therapeutic mechanisms of a mindfulness-based treatment for IBS: effects on visceral 
sensitivity, catastrophizing, and affective processing of pain sensations. J. Behav. Med. 
Dec 8 2011. 
63. 
Goldin PR, Gross JJ. Effects of mindfulness-based stress reduction (MBSR) on emotion 
regulation in social anxiety disorder. Emotion (Washington, D.C.). Feb 2010;10(1):83-91. 
64. 
Houle TT, Butschek RA, Turner DP, Smitherman TA, Rains JC, Penzien DB. Stress and 
sleep duration predict headache severity in chronic headache sufferers. Pain. Dec 
2012;153(12):2432-2440. 
65. 
De Benedittis G, Lorenzetti A. The role of stressful life events in the persistence of 
primary headache: major events vs. daily hassles. Pain. Oct 1992;51(1):35-42. 
66. 
Peroutka SJ. What turns on a migraine? A systematic review of migraine precipitating 
factors. Current pain and headache reports. Oct 2014;18(10):454. 
67. 
Fritsche G, Frettloh J, Huppe M, Dlugaj M, Matatko N, Gaul C, Diener HC. Prevention 
of medication overuse in patients with migraine. Pain. Nov 2010;151(2):404-413. 
68. 
Thorn BE, Pence LB, Ward LC, Kilgo G, Clements KL, Cross TH, Davis AM, Tsui PW. 
A randomized clinical trial of targeted cognitive behavioral treatment to reduce 
catastrophizing in chronic headache sufferers. The journal of pain : official journal of the 
American Pain Society. Dec 2007;8(12):938-949. 

Protocol Template, Version 1.0 
35 of 37 
69. 
Powers SW, Kashikar-Zuck SM, Allen JR, LeCates SL, Slater SK, Zafar M, Kabbouche 
MA, O'Brien HL, Shenk CE, Rausch JR, Hershey AD. Cognitive behavioral therapy plus 
amitriptyline for chronic migraine in children and adolescents: a randomized clinical trial. 
Jama. Dec 25 2013;310(24):2622-2630. 
70. 
Schoen JC, Campbell RL, Sadosty AT. Headache in pregnancy: an approach to 
emergency department evaluation and management. The western journal of emergency 
medicine. Mar 2015;16(2):291-301. 
71. 
Schmidt S, Grossman P, Schwarzer B, Jena S, Naumann J, Walach H. Treating 
fibromyalgia with mindfulness-based stress reduction: results from a 3-armed 
randomized controlled trial. Pain. Feb 2011;152(2):361-369. 
72. 
Goyal M, Singh S, Sibinga EM, Gould NF, Rowland-Seymour A, Sharma R, Berger Z, 
Sleicher D, Maron DD, Shihab HM, Ranasinghe PD, Linn S, Saha S, Bass EB, 
Haythornthwaite JA. Meditation programs for psychological stress and well-being: a 
systematic review and meta-analysis. JAMA Intern Med. Mar 2014;174(3):357-368. 
73. 
Gaylord SA, Palsson OS, Garland EL, Faurot KR, Coble RS, Mann JD, Frey W, Leniek 
K, Whitehead WE. Mindfulness training reduces the severity of irritable bowel syndrome 
in women: results of a randomized controlled trial. Am. J. Gastroenterol. Sep 
2011;106(9):1678-1688. 
74. 
Kabat-Zinn J, Lipworth L, Burney R, Sellers W. Four year follow-up of a meditation-
based program for the self-regulation of chronic pain: treatment outcomes and 
compliance. Clin. J. Pain. 1986;2:159-173. 
75. 
Kabat-Zinn J. Full Catastrophe Living (revised and updated edition): Using the Wisdom 
of Your Body and Mind to Face Stress, Pain, and Illness. New York, NY: Random 
House; 2013. 
76. 
Lutz A, Slagter HA, Dunne JD, Davidson RJ. Attention regulation and monitoring in 
meditation. Trends Cogn Sci. Apr 2008;12(4):163-169. 
77. 
Farb NA, Anderson AK, Segal ZV. The mindful brain and emotion regulation in mood 
disorders. Can. J. Psychiatry. Feb 2012;57(2):70-77. 
78. 
Farb NA, Segal ZV, Anderson AK. Mindfulness meditation training alters cortical 
representations of interoceptive attention. Soc. Cogn. Affect. Neurosci. Jan 2013;8(1):15-
26. 
79. 
Bushnell MC, Ceko M, Low LA. Cognitive and emotional control of pain and its 
disruption in chronic pain. Nature reviews. Neuroscience. Jun 2013;14(7):502-511. 
80. 
Jensen MP. Psychosocial approaches to pain management: an organizational framework. 
Pain. Apr 2011;152(4):717-725. 
81. 
Day MA, Jensen MP, Ehde DM, Thorn BE. Toward a theoretical model for mindfulness-
based pain management. The journal of pain : official journal of the American Pain 
Society. Jul 2014;15(7):691-703. 
82. 
Price DD. Psychological and Neural Mechanisms of Pain. New York, New York: Raven 
Press; 1988. 
83. 
Day MA, Thorn BE, Rubin NJ. Mindfulness-based cognitive therapy for the treatment of 
headache pain: A mixed-methods analysis comparing treatment responders and treatment 
non-responders. Complementary therapies in medicine. Apr 2014;22(2):278-285. 
84. 
Bertisch SM, Wells RE, Smith MT, McCarthy EP. Use of relaxation techniques and 
complementary and alternative medicine by American adults with insomnia symptoms: 
results from a national survey. J. Clin. Sleep Med. Dec 15 2012;8(6):681-691. 
85. 
Erwin Wells R, Phillips RS, McCarthy EP. Patterns of mind-body therapies in adults with 
common neurological conditions. Neuroepidemiology. 2011;36(1):46-51. 
86. 
Purohit MP, Wells RE, Zafonte R, Davis RB, Yeh GY, Phillips RS. Neuropsychiatric 
symptoms and the use of mind-body therapies. J. Clin. Psychiatry. Jun 2013;74(6):e520-
526. 

Protocol Template, Version 1.0 
36 of 37 
87. 
Purohit MP, Wells RE, Zafonte RD, Davis RB, Phillips RS. Neuropsychiatric symptoms 
and the use of complementary and alternative medicine. PM R. Jan 2013;5(1):24-31. 
88. 
Wells RE, Bertisch SM, Buettner C, Phillips RS, McCarthy EP. Complementary and 
alternative medicine use among adults with migraines/severe headaches. Headache. Jul-
Aug 2011;51(7):1087-1097. 
89. 
Wells RE, Phillips RS, Schachter SC, McCarthy EP. Complementary and alternative 
medicine use among US adults with common neurological conditions. J Neurol. Nov 
2010;257(11):1822-1831. 
90. 
John PJ, Sharma N, Sharma CM, Kankane A. Effectiveness of yoga therapy in the 
treatment of migraine without aura: a randomized controlled trial. Headache. May 
2007;47(5):654-661. 
91. 
Tonelli ME, Wachholtz AB. Meditation-based treatment yielding immediate relief for 
meditation-naive migraineurs. Pain Manag. Nurs. Mar 2014;15(1):36-40. 
92. 
Wachholtz AB, Pargament KI. Migraines and meditation: does spirituality matter? 
Journal of behavioral medicine. Aug 2008;31(4):351-366. 
93. 
Wells RE, Kerr CE, Wolkin J, Dossett M, Davis RB, Walsh J, Wall RB, Kong J, 
Kaptchuk T, Press D, Phillips RS, Yeh G. Meditation for adults with mild cognitive 
impairment: a pilot randomized trial. Journal of the American Geriatrics Society. Apr 
2013;61(4):642-645. 
94. 
Wells RE, Yeh GY, Kerr CE, Wolkin J, Davis RB, Tan Y, Spaeth R, Wall RB, Walsh J, 
Kaptchuk TJ, Press D, Phillips RS, Kong J. Meditation's impact on default mode network 
and hippocampus in mild cognitive impairment: a pilot study. Neuroscience letters. Nov 
27 2013;556:15-19. 
95. 
Kabat-Zinn J. Full Catastrophe Living:  Using the Wisdom of Your Body and Mind to 
Face Stress, Pain, and Illness. New York: Random House; 1990. 
96. 
Devilly GJ, Borkovec TD. Psychometric properties of the credibility/expectancy 
questionnaire. Journal of behavior therapy and experimental psychiatry. Jun 
2000;31(2):73-86. 
97. 
Bellg AJ, Borrelli B, Resnick B, Hecht J, Minicucci DS, Ory M, Ogedegbe G, Orwig D, 
Ernst D, Czajkowski S. Enhancing treatment fidelity in health behavior change studies: 
best practices and recommendations from the NIH Behavior Change Consortium. Health 
psychology : official journal of the Division of Health Psychology, American 
Psychological Association. Sep 2004;23(5):443-451. 
98. 
Borrelli B. The Assessment, Monitoring, and Enhancement of Treatment Fidelity In 
Public Health Clinical Trials. Journal of public health dentistry. Winter 2011;71(s1):S52-
S63. 
99. 
Larsen DL, Attkisson CC, Hargreaves WA, Nguyen TD. Assessment of client/patient 
satisfaction: development of a general scale. Evaluation and program planning. 
1979;2(3):197-207. 
100. 
Pbert L, Adams A, Quirk M, Hebert JR, Ockene JK, Luippold RS. The patient exit 
interview as an assessment of physician-delivered smoking intervention: a validation 
study. Health psychology : official journal of the Division of Health Psychology, 
American Psychological Association. Mar 1999;18(2):183-188. 
101. 
Pan PH, Tonidandel AM, Aschenbrenner CA, Houle TT, Harris LC, Eisenach JC. 
Predicting acute pain after cesarean delivery using three simple questions. 
Anesthesiology. May 2013;118(5):1170-1179. 
102. 
Diener HC, Dodick DW, Aurora SK, Turkel CC, DeGryse RE, Lipton RB, Silberstein 
SD, Brin MF. OnabotulinumtoxinA for treatment of chronic migraine: results from the 
double-blind, randomized, placebo-controlled phase of the PREEMPT 2 trial. 
Cephalalgia. Jul 2010;30(7):804-814. 
103. 
Baer RA, Smith GT, Hopkins J, Krietemeyer J, Toney L. Using self-report assessment 
methods to explore facets of mindfulness. Assessment. Mar 2006;13(1):27-45. 

Protocol Template, Version 1.0 
37 of 37 
104. 
Gratz KL, Roemer L. Multidimensional assessment of emotion regulation and 
dysregulation: development, factor structure, and initial validation of the difficulties in 
emotion regulation scale. Journal of Psychopathology and Behavioral Asseessment. 
2004;26:41-54. 
105. 
McCracken LM, Vowles KE, Eccleston C. Acceptance of chronic pain: component 
analysis and a revised assessment method. Pain. Jan 2004;107(1-2):159-166. 
106. 
Herth K. Development and refinement of an instrument to measure hope. Scholarly 
inquiry for nursing practice. Spring 1991;5(1):39-51; discussion 53-36. 
107. 
Scheier MF, Carver CS, Bridges MW. Distinguishing optimism from neuroticism (and 
trait anxiety, self-mastery, and self-esteem): a reevaluation of the Life Orientation Test. 
Journal of personality and social psychology. Dec 1994;67(6):1063-1078. 
108. 
Kosinski M, Bayliss MS, Bjorner JB, Ware JE, Jr., Garber WH, Batenhorst A, Cady R, 
Dahlof CG, Dowson A, Tepper S. A six-item short-form survey for measuring headache 
impact: the HIT-6. Qual Life Res. Dec 2003;12(8):963-974. 
109. 
Kawata AK, Coeytaux RR, Devellis RF, Finkel AG, Mann JD, Kahn K. Psychometric 
properties of the HIT-6 among patients in a headache-specialty practice. Headache. Jun 
2005;45(6):638-643. 
110. 
Yang M, Rendas-Baum R, Varon SF, Kosinski M. Validation of the Headache Impact 
Test (HIT-6) across episodic and chronic migraine. Cephalalgia. Feb 2011;31(3):357-
367. 
111. 
Stewart WF, Lipton RB, Dowson AJ, Sawyer J. Development and testing of the Migraine 
Disability Assessment (MIDAS) Questionnaire to assess headache-related disability. 
Neurology. 2001;56(6 Suppl 1):S20-28. 
112. 
Stewart WF, Lipton RB, Whyte J, Dowson A, Kolodner K, Liberman JN, Sawyer J. An 
international study to assess reliability of the Migraine Disability Assessment (MIDAS) 
score. Neurology. Sep 22 1999;53(5):988-994. 
113. 
French DJ, Holroyd KA, Pinell C, Malinoski PT, O'Donnell F, Hill KR. Perceived self-
efficacy and headache-related disability. Headache. Sep 2000;40(8):647-656. 
114. 
Jhingran P, Davis SM, LaVange LM, Miller DW, Helms RW. MSQ: Migraine-Specific 
Quality-of-Life Questionnaire. Further investigation of the factor structure. 
Pharmacoeconomics. Jun 1998;13(6):707-717. 
115. 
Martin BC, Pathak DS, Sharfman MI, Adelman JU, Taylor F, Kwong WJ, Jhingran P. 
Validity and reliability of the migraine-specific quality of life questionnaire (MSQ 
Version 2.1). Headache. Mar 2000;40(3):204-215. 
116. 
Cohen S, Kamarck T, Mermelstein R. A global measure of perceived stress. Journal of 
health and social behavior. Dec 1983;24(4):385-396. 
117. 
Myers SS, Phillips RS, Davis RB, Cherkin DC, Legedza A, Kaptchuk TJ, Hrbek A, 
Buring JE, Post D, Connelly MT, Eisenberg DM. Patient expectations as predictors of 
outcome in patients with acute low back pain. J Gen Intern Med. Feb 2008;23(2):148-
153. 
118. 
Penzien DB. Guidelines for trials of behavioral treatments for recurrent headache: 
purpose, process, and product. Headache. May 2005;45 Suppl 2:S87-89.