Mind-body Treatments for Chronic Back Pain
Phase: NA
Conditions: Chronic Pain, Back Pain Lower Back Chronic, Back Pain, Low
Sponsor: University of Colorado, Boulder

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TITLE:  Mind-body treatments for chronic back pain 
 
PROTOCOL VERSION DATE: September 5, 2018 
VERSION: 4.4 
 
NCT03294148 
PRINCIPAL INVESTIGATOR (PI):  
Name: Tor Wager 
Address: 345 UCB 
Telephone: (303)895-8739 
Email: tor.wager@colorado.edu 
KEY PERSONNEL 
Name: Tor Wager 
Role in project: PI 
 
 
Name: Jonathan Ashar 
Role in project: Co-investigator with edit 
 
Name: Sona Dimidjian 
Role in project: Co-investigator 
 
Name: Daniel Ott 
Role in project: Co-investigator 
 
Name: Thomas Flood 
Role in project: Co-investigator 
  
Name: Howard Schubiner 
Role in project: Co-investigator 
 
Name: Alan Gordon 
Role in project: Co-investigator 
  
Name: Daniel Lyman 
Role in project: Co-investigator 
  

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Name: Judith Carlisle 
Role in project: Co-investigator 
 
Name: Joseph Clark 
Role in project: Co-investigator 
 
Name: David Messinger 
Role in project: Co-investigator 
 
Name: Christie Uipi 
Role in project: Co-investigator 
 
Name: Ed Walton 
Role in project: Co-investigator 
 
Name: Karen Knight 
Role in project: Co-investigator 
 
Name: Zachary Anderson 
Role in project: Co-investigator 
 
Name: Laurie Polisky 
Role in project: Co-investigator 
 
Name: Jordan Griffin 
Role in project: Research coordinator 
 
Name: Daniel Kusko 
Role in project: Research assistant 
 
Name: Victoria Schelkun 
Role in project: Research assistant 
I. 
OBJECTIVES 
Hypotheses: 
1) Non-deceptive, transparently administered placebo treatment can provide clinically meaningful 
relief of chronic back pain (CBP) 
2) Psychotherapy including a novel psychoeducational component can provide clinically 
meaningful relief of chronic back pain (CBP) 
3) Brain systems supporting learning about pain will be altered in CBP patients 
 
Specific Aims: 
1) To test the efficacy of a safe, non-deceptive, transparently administered placebo treatment for 
chronic back pain (CBP) relative to waitlist.  Outcomes include self-report measures of pain and 
functioning, and measures of brain and immune function.   

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2) To test the efficacy of psychotherapy including a novel psychoeducational component for 
chronic back pain (CBP) relative to waitlist.  Outcomes include self-report measures of pain and 
functioning, and measures of brain and immune function.   
3) To characterize brain systems supporting learning about pain in CBP patients 
 
II. 
BACKGROUND AND SIGNIFICANCE  
Placebo treatments provide a window into the therapeutic encounter. Because they are 
pharmacologically inert, the effects of placebo treatments on the body are mediated by the patient’s 
mind and brain.  Placebo effects are caused by the treatment context, including the supportive care 
provided during the therapeutic encounter (Kaptchuk, 2002; F. G. Miller & Kaptchuk, 2008; Wager & 
Atlas, 2015), and can be estimated by comparing placebo and no-treatment control groups. Recent 
studies (Kam-Hansen et al., 2014; Kaptchuk et al., 2010; Kelley, Kaptchuk, Cusin, Lipkin, & Fava, 2012), 
including one from our group (Schafer, Colloca, & Wager, 2015), suggest that a transparently prescribed 
“open-label” placebo can provide effective pain relief—even though participants know they are 
receiving an inert treatment. Importantly, the treatment is non-deceptive, and thus can ethically be 
administered to patients in clinical settings (Blease, Colloca, & Kaptchuk, 2016).  Patients believe that 
open-label placebo treatments are ethical and can be therapeutic (Hull et al., 2013; Ortiz, Chandros Hull, 
& Colloca, 2016; Tilburt, Emanuel, Kaptchuk, Curlin, & Miller, 2008).  By comparing open-label placebo 
treatment with a no-treatment control group, one can assess the effects of the therapeutic encounter 
independent of beliefs in the specific treatment itself.  This is the goal of the present study.   
 
Chronic low back pain is, in many respects, an ideal domain for investigating clinical effects of the 
therapeutic encounter.  It is debilitating and highly prevalent: Low back pain is a leading cause of 
disability in the industrialized world, with lifetime prevalence estimates ranging from 50 to 80% (Cohen, 
Argoff, & Carragee, 2008; Freburger et al., 2009). Thus, both the availability of patients and the impact 
of placebo studies on back pain are high.  Back pain is also influenced by placebo treatments such as 
sham acupuncture or placebo pills in previous clinical studies (Haake et al., 2007; Hashmi, Baria, et al., 
2012; Hashmi, Baliki, et al., 2012; Tuttle et al., 2015).  However, only one study to our knowledge has 
compared placebo to a no treatment condition (Müller et al., 2016), which is necessary to differentiate 
placebo effects from other factors, like regression to the mean.  Further, open-label placebo treatment 
is a new frontier.   
 
Among treatments for back pain, steroid injection for pain is a medical procedure well suited to placebo 
studies. Steroid injection is the single most commonly performed intervention for back pain in the 
United States, with more than 2 million being performed in 2008 for Medicare patients alone 
(Manchikanti et al., 2012). Our collaborator at the Panorama Orthopedics and Spine Center, Dr. Karen 
Knight, performs several dozens such injections each month.   But surprisingly, despite its prevalence, a 
recent meta-analysis concluded that steroid injection is no more effective than placebo injections 
(Bicket, Gupta, Brown, & Cohen, 2013). The beneficial results that have led to its widespread use are 
likely due to the therapeutic encounter and injection procedure itself; the steroid is superfluous.  For 
these reasons, we have chosen a placebo injection procedure (subcutaneous saline injection into the 
lower back) for the current study. 
 
Additionally, cognitive behavioral psychotherapies have established efficacy for CBP, with meta-analyses 
estimating small to medium sized effects relative to no treatment (Cherkin et al., 2016; Hoffman, Papas, 

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Chatkoff, & Kerns, 2007).  Here, we test a novel psychotherapy that builds off existing psychotherapeutic 
approaches.  Most patients with CBP have no pathology in the back that can be identified as the cause 
of pain (Chou, 2007; Deyo et al., 2014).  In other words, medical examination reveals that the back 
appears fundamentally healthy and intact, rather than damaged. Here, we will test a psychotherapy 
intervention that helps patients consider whether their back is healthy or damaged, and suggests that if 
the back is healthy, the pain is a false alarm that does not connote harm. 
 
In this study, we will provide the first answers to questions that could influence medical training and 
practice.  Are open-label subcutaneous placebo injections into the back effective in relieving pain, and 
do they produce objective, physiological evidence of pain relief?  Such physiological evidence is needed, 
as self-reported pain is subject to several biases, including demand characteristics (patient compliance 
with perceived research objectives), which may be especially prominent in open-label placebo trials.  
Additionally, we will test a novel psychotherapy that has the potential to significantly advance the 
treatment of CBP. 
 
Physiological measures of pain relief will be provided by brain MRI and measures of immune function.  
In CBP, structural and functional MRI of the brain have documented reliable changes in resting state 
activity, responses to experimentally induced pain, and gray matter density relative to healthy controls 
(Kregel et al., 2015).  Further, functional and structural MRI measures can normalize after successful 
treatment for back pain (Seminowicz et al., 2011; Shpaner et al., 2014).  These measures have also been 
shown to track the natural course of recovery vs. chronification of acute back pain (Baliki et al., 2012; 
Hashmi et al., 2013; Vachon-Presseau et al., 2016).  The immune system is also a central contributor to 
chronic pain (Grace, Hutchinson, Maier, & Watkins, 2014).  Two previous studies have reported that 
peripheral (blood) measures of inflammation reflect the severity of CBP (Pedersen, Schistad, Jacobsen, 
Røe, & Gjerstad, 2015) and predict the future course of CBP (Schistad et al., 2014).  
 
A second, related aim of this study is to investigate pain learning-related brain function in CBP patients.  
Chronic pain is closely tied to dysfunctional pain expectancy and pain avoidance learning (Gatchel, Peng, 
Peters, Fuchs, & Turk, 2007; Jensen, Ehde, & Day, 2016).  Recent work from our group (Roy et al., 2014) 
and others (Delgado, Li, Schiller, & Phelps, 2008; Eldar, Hauser, Dayan, & Dolan, 2016; Seymour et al., 
2005) has begun to identify the prefrontal, striatal, and brainstem systems supporting pain avoidance 
learning in healthy samples using fMRI.  Broad differences in these brain systems have also been 
observed in chronic pain (Baliki et al., 2012; Bushnell, Ceko, & Low, 2013; Hashmi et al., 2013; Lee et al., 
2015; Seminowicz et al., 2011; Vachon-Presseau et al., 2016), but their specific role in chronic pain is 
unknown.  Here, we propose to investigate alterations in prefrontal-striatal-brainstem systems 
supporting pain avoidance learning in chronic pain patients.  This area has been relatively understudied.  
Advances along this front may make critical contributions to our understanding of chronic pain.  We 
additionally will test whether the treatment alters these pain avoidance learning systems, relative to 
waitlist. 
 
Additionally, electroencephalography (EEG) provides a potentially promising measurement channel for 
developing brain markers of pain intensity (Davis et al., 2017). EEG markers of pain intensity have 
expanded translational value relative to fMRI, as EEG is cheap, portable, quick, and easily administered.  
Existing work points to altered EEG signals in chronic pain (Ploner, Sorg, & Gross, 2016).  However, 
previous studies have not investigated EEG responses to different intensities of evoked chronic back 
pain.  Here, we measure EEG while evoking back pain of different intensities, which may facilitate the 
development of an EEG marker for chronic pain intensity.   

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III. 
PRELIMINARY STUDIES 
Our laboratory has extensive expertise in functional magnetic resonance imaging of placebo analgesia 
and pain (Geuter & Büchel, 2013; Geuter, Eippert, Hindi Attar, & Büchel, 2013; Wager et al., 2004, 2013; 
Wager, Atlas, Leotti, & Rilling, 2011).  A previous study from our laboratory demonstrated placebo 
analgesia in acute experimental pain even when participants know the treatment is inert (a placebo) 
(Schafer et al., 2015).  We have also conducted numerous studies administering acute pain stimulations 
to participants (Atlas, Bolger, Lindquist, & Wager, 2010; Colloca, Petrovic, Wager, Ingvar, & Benedetti, 
2010; Koban & Wager, 2015), including a currently ongoing study administering pressure pain 
stimulations with the same device as proposed here (IRB protocol #15-0483). Co-I Sona Dimidjian has 
much experience conducting randomized controlled psychotherapy trials (i.e., Dimidjian et al., 2006, 
2015; Shallcross et al., 2015), and Co-I Howard Schubiner has previously conducted randomized 
controlled trials of psychotherapy for chronic pain (Hsu et al., 2010).  And, our other collaborators have 
previously used EEG to identify brain correlates of chronic pain (Prichep, Shah, Merkin, & Hiesiger, 
2017). 
IV. 
RESEARCH STUDY DESIGN  
Study design:  The study design is presented in the following figure.  Participants with chronic 
back pain will complete an online prescreen.  Those who are likely eligible will then be randomized to 
one of two parallel studies, with randomization stratified on pain intensity, age, gender, and opioid use.  
The first study compares a placebo treatment to waitlist, and the second study compares a 
psychotherapy treatment to waitlist (Figure, panel A).   We do not use a standard three-way 
randomization (psychotherapy vs. placebo vs. waitlist) since we want participants receiving the placebo 
treatment to believe they are getting the active treatment, not a control treatment (which is the usual 
function of the placebo in a study).  Beliefs and expectations are central to placebo effects (Ashar, 
Chang, & Wager, 2017), so we constrain participant’s expectations in the placebo vs. waitlist study to 
necessarily think they are in the active treatment arm.   
Patients in both studies will undergo identical study procedures (Figure, panel B). The one 
exception is which treatment they receive—placebo injection or a psychotherapy treatment, depending 
on to which study they are randomized.  Thus, for the remainder of this protocol, we discuss both 
studies as one.  We simply refer to “the treatment” to refer to placebo or to psychotherapy (depending 
on the study).  The only place we describe the two studies separately is regarding the treatment 
procedures; all other descriptions apply identically to both studies. 
We plan to combine data from both studies in the data analysis phase, since patients in both 
studies complete identical study procedures (besides the treatment administered).  To allocate subjects 
efficiently, patients will be randomized 2:1 treatment to waitlist.  This will result in three equally sized 
groups—placebo, psychotherapy, and waitlist—for the analysis phase.   
After patients are randomized to study, we will call them and describe the study, including 
which treatment they might receive.  Interested patients will then complete an in-person eligibility 
session, and eligible participants will be scheduled for the baseline assessment session.  Following the 
baseline assessment session, participants will then be randomized to the treatment group or the waitlist 
group (with a ratio of 2:1 treatment:waitlist), using a computer-generated random sequence. The wait-
list group is needed to isolate treatment effects from the effects of time and any effects associated with 
simply enrolling in a study.  Thus, patients are randomized twice:  first to study (placebo or 
psychotherapy study), and then, within study, to treatment vs. waitlist. 
 
Participants randomized to treatment will be scheduled for treatment.  Approximately one 
month after the baseline assessment session, all participants will return for a second assessment.  After 

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this second, post-treatment assessment, participants who were on the waitlist in the placebo study will 
be offered the option of receiving the open-label placebo treatment.  Participants who were on the 
waitlist in the psychotherapy study will be offered a chronic pain self-help book (Unlearning your Pain, 
written by Howard Schubiner) and free access to an online chronic pain self-help program based on the 
psychotherapy treatment (total market value: ~$125).  Receiving the treatment will be optional for 
waitlisted participants. 
A brief follow-up survey will be sent at months 1, 2, 3, 6, and 12 after the final assessment 
session.  These will provide longer term data about the trajectory and durability of patient 
improvement. 
 
Additionally, a group of healthy controls, with no history of back pain, will complete the baseline 
assessment (Figure, panel C).  They will serve as a comparison group for brain activity related to the 
novel back pain device and task described below.  Healthy controls will have only one in-person session. 
 
 

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Figure.  Study design.  A)  First stage of randomization:  patients are randomized to study.  B)  
 
A description of each session is provided in the Procedures section below. 
 
Sample size:  We will randomize N = 150 patients in the study, 50 per treatment group.  Since we 
estimate a ~15% rate of attrition/technical problems, we estimate this will yield a sample of N = 126 
completers (about N = 42 per group).  We estimate that an additional N = 25 patients will be enrolled in 
the study but will not be randomized to a treatment group for a variety of reasons (e.g. no shows to the 
baseline scan, decisions to withdraw after the baseline scan).  Additionally, we will enroll N = 65 healthy 
controls to target N = 50 controls with high quality fMRI data.   
 
 
Power analysis:  Effect size estimates come from two sources.  First, four previous trials comparing 
sham acupuncture (i.e., placebo) to no treatment found an average placebo effect size of d = -0.68 (95% 
CI -0.85 to -0.50) (Hróbjartsson & Gøtzsche, 2010).  Second, a previous trial of open-label placebo for 
irritable bowel syndrome found an effect of d = -.79 relative to no treatment (Kaptchuk et al., 2010).  
These two effect sizes require two groups each of sizes n = 44 and n = 33, respectively for each effect 
size estimate, to yield 80% power at two-tailed α = .05.  Thus, with a sample of N = 42 completers per 
group, we estimate that our study will have approximately 80% power, assuming the effect size of the 
placebo treatment in this study is in the range of what was reported in these previous studies.  The 
psychotherapy is expected to have an effect size at least as large as the placebo treatment, since 
psychotherapy includes placebo effects in addition to other treatment components (Ashar et al., 2017). 
 

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Study length:  The study will take 2 - 3 months for each participant (not including follow-up online 
surveys, the last of which will be sent 1 year later), and 2 years to complete data collection.  
 
Data analysis plan:  The primary outcome is pain intensity, as measured by the Brief Pain Inventory 
– Short Form (BPI-SF).  We choose pain intensity as the primary outcome as it is the main target for both 
the placebo treatment and the psychotherapy, and pain intensity may be most relatable to the brain 
measures collected.  We will use the mean value of the four BPI-SF pain intensity questions, or, if the 
mean BPI-SF score is highly correlated with the single BPI-SF item measuring average pain over the last 
week, we will use that single “average pain” item.  The “average pain” item is a more interpretable 
outcome to a broad audience (Pek et al., 2018), and it aligns with our operationalization of “remission” 
below.   
 
The primary endpoint of the trial is the post-treatment MRI session, approximately 5 weeks after the 
baseline assessment and randomization.  Follow up measures are collected for one year following the 
post-treatment assessment and may be included in the main analysis or presented in a separate 
manuscript.  Secondary analyses will investigate pain intensity each week during the treatment phase, 
to explore the time courses of treatment responses.  One question of special interest is the durability of 
the placebo response (Ashar et al., 2017).  Pain reduction may peak soon after the placebo treatment 
and diminish by the time of the primary endpoint, perhaps because a common lay concept of steroid 
injections is that they provide time-limited pain relief.   
 
Treatment effects will be estimated using mixed models, which are considered to be well suited for 
handling missing data.  For all analyses, waitlisted participants from both studies (i.e., psychotherapy 
waitlist and placebo waitlist patients) will be combined into one waitlist group.  Secondary outcomes will 
be analyzed in a similar manner as the primary outcome. 
   
Clinical significance will be determined by calculating the percentage of patients in each condition 
who meet the following criteria regarding pain reduction from baseline: at least 30% reduction in pain 
intensity, at least 50% reduction in pain intensity, and “pain free or nearly pain free”—defined as 
average pain intensity of 0 or 1 over the past week (on the single BPI-SF item measuring average pain 
over the last week).  
 
Primary analyses will be conducted on an intent-to-treat (ITT) sample, and if necessary, the ITT 
sample will be modified by excluding any randomized patients who are found not to meet study criteria 
(e.g., patients unable or unwilling to initiate the treatment or control group they are randomized to). 
Secondary analyses will be conducted on a per protocol (“completer”) sample.  
 
We will test three contrasts of particular theoretical interest rather than conducting an omnibus test 
(Rosenthal et al, 2000; Steiger 2004; Judd et al. 2009).  The three planned comparisons are: 1) 
psychotherapy vs. placebo, to estimate psychotherapy effects relative to a control treatment, 2) placebo 
vs. waitlist, to estimate placebo effects, and 3) psychotherapy vs. waitlist, which provides a benchmark 
for comparing our findings to the broader literature, and which may be the most practically relevant 
question (e.g., what benefit might a patient expect from enrolling in this psychotherapy). Reporting of 
results will emphasize estimation of effect size rather than rejection of null hypotheses (Cumming, 2013; 
Pek et al. 2018). 
 
To create study groups that are matched across covariates of no interest we will use a minimization 
procedure.  Minimization is regarded as an optimum assignment procedure for studies with relatively 

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small sample sizes that seek to balance groups on several covarites (Hu, Hu, Ma, & Rosenberger, 2014; 
Lin & Su, 2012).  Covariates that will be balanced on are baseline pain, age, gender, and opioid use.  The 
minimization algorithm we will use (Xiao, Yank, & Ma, 2012) handles continuous covariates (age, pain), 
so these variables will not be stratified. We will control for baseline scores of these covariates in 
analyses, as described above, although the minimization algorithm is likely to evenly balance these 
covariates across groups.  We will minimize patients twice:  first, to study; second, to treatment or 
waitlist within-study (Figure 1).  Although disability is a co-primary outcome measure, we do not balance 
group assignment on disability.  This is because it is not measured in the eligibility pre-screening form 
(since it is not an inclusion criteria), and thus cannot be used to assign patients to study, which happens 
upon completion of the eligibility pre-screening form.  
 
 
fMRI images will be preprocessed and analyzed using standard in-house tools (c.f. Wager et al., 
2013) and other existing toolboxes (i.e., SPM, Conn).  A secondary goal of the study is to identify 
patterns of brain activity that track subjective back pain intensity (pre-treatment) using a penalized 
regression model to handle correlated predictors (brain voxels).  Our research group has developed 
several such patterns accurately tracking pain intensity (Wager et al., 2013) and other affective states 
(Ashar, Andrews-Hanna, Dimidjian, & Wager, 2016; Chang, Gianaros, Manuck, Krishnan, & Wager, 2015; 
Krishnan et al., 2016), and similar methods will be used to develop a back pain pattern in this study.  
Pattern intensity scores (indicating to what extent the back pain-related pattern of brain activity is 
expressed) will be submitted to a group by time interaction via a repeated-measures ANOVA test to test 
for treatment effects. Analyses of resting state data will follow previous studies of resting state brain 
function in chronic back pain (reviewed in Kregel et al., 2015). Additionally, we will conduct a group by 
time interaction for pain-related brain activity at each brain voxel independently, with corrections for 
multiple comparisons (Genovese, Lazar, & Nichols, 2002), as is standard practice in the field. 
 
Another secondary goal is to determine the relationship between measures of immune function and 
chronic back pain, as various measures of immune function have been previously associated with 
chronic pain (see Background and Significance).  These data be analyzed by Dr. Michael Irwin (UCLA) and 
Dr. Mark Hutchinson (University of Adelaide, Australia), who are both collaborators with expertise in this 
domain (Grace et al., 2014; Irwin & Miller, 2007; Kwok et al., 2013).  We will send blood samples that 
have been de-identified (i.e., tagged only with a random ID, not with any identifying information).  Only 
measures of immune system function will be extracted from these samples, and then they will be 
destroyed. The relationship between the measures of immune function and chronic back pain will be 
analyzed for group by time interactions via a repeated-measures ANOVA test.  Primary markers of 
immune function that can be extracted from blood samples include IL-6 (E. M. Miller & McDade, 2012), 
and potentially other immune markers as well (Skogstrand et al., 2005) depending on the technology 
that will be available to our collaborators at the time of analysis.  Age, gender, and opioid use will also 
be included as covariates in analyses of immune function due to potential influence of these factors on 
immune function. 
 
Another secondary goal is to develop an EEG marker of chronic pain intensity.  EEG data will be filtered 
and cleaned using standard procedures (e..g, Prichep et al., 2017).  We will use machine learning 
techniques, as described for the fMRI analyses above, to identify patterns of brain activity across 
electrodes that predict pain intensity. 
V. 
FUNDING 

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This research is being funded by the Study of the Therapeutic Encounter Foundation, the Radiological 
Society of North America, and by the Psychophysiologic Disorders Society. 
VI. 
ABOUT THE SUBJECTS  
 
Subject Population(s) 
Number to be randomized to each group  
Chronic back pain community sample—
placebo treatment 
50 
Chronic back pain community sample—
placebo waitlist 
25 
Chronic back pain community sample—
psychotherapy 
50 
Chronic back pain community sample—
psychotherapy waitlist 
25 
Healthy controls 
25 
 
We anticipate enrolling 240 participants (N = 150 patients randomized to treatment group, N = 25 
patients who enroll but are never randomized, and N = 65 healthy controls), 176 of whom we anticipate 
will complete the study (N = 126 patients, N = 50 healthy controls completing). 
 
Inclusion criteria:   
 
• 
Participants aged 21 to 70 with CBP will be enrolled.  
• 
CBP will be defined according to the criteria established by a recent NIH task force (Deyo et al., 
2014).  Pain duration must be at least 3 months, with back pain being an ongoing problem for at 
least half the days of the last 6 months.  That is, patients can meet criteria by either reporting 
pain every day for the past 3 months, or by reporting pain on half or more of the days for the 
past 6+ months.  This will be determined by asking patients:  (1) How long has back pain has 
been an ongoing problem for you? (2) How often has low back pain been an ongoing problem 
for you over the past 6 months? A response of greater than 3 months to question 1 and a 
response of ‘‘at least half the days in the past 6 months’’ to question 2 would define CBP. 
• 
Patients must rate pain intensity at 4/10 or greater on the Brief Pain Inventory-Short Form (BPI-
SF) (on the item measuring average pain over the last week), in keeping with inclusion criteria 
from previous CBP trials (Baliki et al., 2012; Cherkin et al., 2016; Hashmi et al., 2013; Seminowicz 
et al., 2011).  Since pain intensity fluctuates from week to week for many CBP patients, we will 
assess patients’ pain intensity twice (at the online pre-screen and a few days prior to their 
eligibility session, described further below) to increase the likelihood that patients’ pain 
intensity is at least 4/10 at the baseline pre-treatment brain scan.  Patients must endorse 4/10 
pain at both these measurements to be eligible.  After endorsing 4/10 pain at both these 
measurements, changes in pain report at later study time points will not serve as basis for 
exclusion. 
• 
Back pain must be elicited by our back pain device (see below). 
• 
Participants must also be comfortable and able to communicate via email or text message, as 
several study measures are collected in this manner (see below). 

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Exclusion criteria: 
• 
Back pain associated with compensation or litigation issues as determined by self-report within 
the past year. 
• 
Leg pain is greater than back pain.  This suggests neuropathic pain, which may be less responsive 
to placebo or psychotherapy. 
• 
Difficulty participating for technical/logistical issues (e.g., unable to get to assessment sessions). 
• 
Self-reported diagnoses of schizophrenia, multiple personality disorder, or dissociative identity 
disorder. 
• 
Self-reported use of intravenous drugs, due to concerns about infections and subject 
compliance with experimental protocols. 
• 
Inability to undergo MRI as determined by MRI safety screen (e.g., pregnancy, metal in body, 
claustrophobia, using the standard screen conducted by the MRI imaging facility). 
• 
Hypersensitive or hyposensitive to pressure pain: unable to tolerate 7kg/cm2 stimulation or 
reporting no pain for 4kg/cm2 stimulation; see further details below. 
• 
Current regular use of an immunosuppressant drug, such as steroids.  Such drugs interfere with 
immunoassay results. 
• 
Self-reported history of metastasizing cancers—cancer of the breast, thyroid, lung, kidney, 
prostate or blood cancers.  
• 
Self-reported history of stroke, brain surgery, or brain tumor. 
• 
Self-reported diagnosis of a specific inflammatory disorder: rheumatoid arthritis, polymyalgia 
rheumatica, scleroderma, Lupus, or polymyositis.  
• 
Unexplained, unintended weight loss of 20 lbs. or more in the past year.  
• 
Cauda Equina syndrome, as screened for by self-reported inability to control bowel or bladder 
function. 
 
Patients enrolled in the study will continue their normal pharmacological and psychosocial treatment for 
pain.  Patients will also agree not to change, add, or remove any of their current treatments during 
course of study, unless indicated otherwise by their physician.  Patients will also agree not to make any 
large lifestyle changes (e.g., diet or exercise) during the course of the study.  Patients will be asked to 
notify the study team of changes to their medication and treatments. 
 
We will also recruit a healthy control group as a comparison group for the back pain fMRI task and other 
tasks.  Inclusion and exclusion criteria for healthy controls are identical to inclusion/exclusion criteria for 
patients, besides back pain.  Healthy controls will be enrolled to match the patient group on mean age 
and on gender ratio. 
 
Inclusion criteria for healthy controls: 
• 
Aged 21 – 70. 
• 
Participants must also be comfortable and able to communicate via email or text message. 
 
Exclusion criteria for healthy controls: 
• 
Self-reported history of back pain lasting more than 2 weeks. 
• 
Self-reported history of any chronic pain diagnosis. 
• 
Difficulty participating for technical/logistical issues (e.g., unable to get to assessment sessions). 
• 
Self-reported diagnoses of schizophrenia, multiple personality disorder, or dissociative identity 
disorder. 

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• 
Self-reported use of intravenous drugs, due to concerns about infections and subject 
compliance with experimental protocols. 
• 
Inability to undergo MRI as determined by MRI safety screen (e.g., pregnancy, metal in body, 
claustrophobia, using the standard screen conducted by the MRI imaging facility). 
• 
Hypersensitive or hyposensitive to pressure pain: unable to tolerate 7kg/cm2 stimulation or 
reporting no pain for 4kg/cm2 stimulation; see further details below. 
• 
Current regular use of an immunosuppressant drug, such as steroids.  Such drugs interfere with 
immunoassay results. 
• 
Self-reported history of metastasizing cancers—cancer of the breast, thyroid, lung, kidney, 
prostate or blood cancers.  
• 
Self-reported history of stroke, brain surgery, or brain tumor. 
• 
Self-reported diagnosis of a specific inflammatory disorder: rheumatoid arthritis, polymyalgia 
rheumatica, scleroderma, Lupus, or polymyositis.  
• 
Unexplained, unintended weight loss of 20 lbs. or more in the past year.  
• 
Cauda Equina syndrome, as screened for by self-reported inability to control bowel or bladder 
function. 
 
VII. 
VULNERABLE POPULATIONS 
None. 
VIII. 
RECRUITMENT METHODS 
Patients will be recruited in four ways:  1) referral from pain management providers, 2) advertisement 
via flyers, electronic bulletin boards, local listservs relevant to chronic pain (i.e., chronic pain patient 
groups listervs), local newspapers, and social media sites such as Facebook (described further below), 3) 
direct contact: patients who contact our research group inquiring about chronic pain research will be 
informed about the present study, 4) advertising through Google (described further below).   
 
We attach to this protocol seven recruitment materials: a flyer, an online posting, a newspaper ad, a 
Facebook ad, a pamphlet for providers to give interested patients, the Google advertisement,and a 
screen capture of a study webpage providing an overview of the study and a link to the pre-screening 
document.  Recruitment materials will describe the treatment as a “novel mind-body treatment”.  The 
nature of the treatment (placebo or psychotherapy, depending on participant randomization) will be 
explained to patients when they come in for the eligibility session (see below) to avoid confusion and 
misunderstanding, given the unusual and potentially confusing nature of placebo treatments.  The flyer 
contains a link, which will take participants to a webpage that provides a brief overview of the study as 
well as a link to the REDCap online eligibility pre-screening document.   
 
Facebook advertising will target subjects in the Boulder-Denver area in the eligible age range.  Ads may 
be targeted to subjects who are “known or likely buyers of pain relief products” as determined by 
Facebook analyses that allow advertisers to target specific populations.  The Facebook ad will link to a 
webpage that provides a brief overview of the study a well as a link to the REDCap online eligibility pre-
screening document.  The Facebook ad will be posted by a Facebook Page created for the study.  This 
Page will display only approved recruitment materials (i.e., approved flyers and recruitment blurbs).  The 

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Facebook ad will be as attached (please see Facebook Ad.pdf), and the back pain image will be randomly 
chosen from stock back pain images provided by Facebook (please see Facebook Example Images.pdf). 
 
We will also advertise using the Google AdWords platform.  The advertisement (attached) will be shown 
to subjects in the Boulder-Denver area who are searching on Google for terms related to back pain (e.g., 
“sore back”, “back pain relief”).  The Google ad will link to a webpage that provides a brief overview of 
the study as well as a link to the REDCap online eligibility pre-screening document.  The Google ad 
includes only text, no images. 
 
Individuals who contact our study will be sent an online eligibility pre-screen form (see attached), which 
was designed in accordance with the Pre-Screening Guidance Document.  Patients who pass the pre-
screen (i.e., who endorse at least 4/10 pain and meet other study criteria) will be randomized to either 
the placebo study or the psychotherapy study and will be scheduled for an eligibility session. At the 
eligibility session, the “Provider pamphlet” document will be used to explain what a placebo is to 
patients in the Placebo study and how it might relieve back pain. This is the first randomization for 
patients.  Later, patients are randomized a second time, to treatment or waitlist, described further 
below and in Study Design above. 
 
Patients who do not pass the pre-screen will be emailed a list of treatment referral options (attached to 
this protocol).  Patients who provided ambiguous information on the online pre-screen may be called or 
emailed with clarifying questions. Dr. Sona Dimidjian, a licensed psychotherapist, will provide clinical 
supervision as needed for these calls when related to mental health conditions. 
 
Healthy controls will be recruited through the general recruitment protocol used in the Wager lab 
(approved IRB protocol #10-0243, title: Screening protocol for pain studies).  This protocol describes the 
recruitment and screening of healthy subjects for pain fMRI studies, which describes the experience of 
healthy controls in this study.  This protocol describes recruitment through fliers on university bulletin 
boards, university mailing lists (e.g., Buff Bulletin), newspaper ads and online bulletin boards such as 
craigslist. Potential subjects will be directed to email Screening Coordinators for more information and 
to undergo eligibility prescreening with a REDCap survey.   
 
Undue influence and coercion are avoided because subjects must initially contact us, and then must 
complete the online pre-screen of their own volition in their own homes, with no pressure from the 
study team.  During the eligibility session, it will be emphasized that participants are free not to continue 
with the study, and that they may also take some time to think about whether they want to participate. 
 
 
List recruitment methods/materials and attach a copy of each in eRA 
1. Flyer 
2. Online bulletin board posting 
3. Pamphlet for providers to give to potential participants with referral information 
4. Facebook recruiting 
5. Local newspapers 
6. Local email listservs 
IX. 
COMPENSATION  

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All participants will be paid $50 for an eligibility session with EEG or $25 for an eligibility session 
without EEG, $75 for each MRI session, and $5 for each follow-up survey completed (total of 5 
follow-up surveys sent).  Participants would thus earn up to $225 for completing this study with 
EEG, or $200 without EEG. Participants will be paid only for visits they have completed. 
Participants deemed ineligible or decide they are not interested in the study at the eligibility 
session will be paid $25 or $50 if they completed the EEG collection.   
Participants will also be given an option to receive a 3D print-out of their brain instead of the $75 
payment for one of the MRI sessions.  Our lab has recently developed the capacity for 3D 
printing of brains.  The market cost of a 3D brain print-out is over $250 (for people who already 
have a brain image, which we will give to our participants freely).  Participants who choose this 
option would thus be paid up to $125 and will receive a 3D brain printout as well. 
Participants can also earn several dollars at each assessment session from the progressive 
ratio button pressing task and from the willingness to experience pain task.  The exact amount 
will vary depending on participants’ choices, but is estimated to be $0 - $5 for the progressive 
ratio task and is $0 - $10 for the willingness to experience pain task, at each of the pre- and 
post-treatment assessment sessions.  
All payment will be in cash given at the conclusion of the participant’s final assessment session, 
except for the payment for the follow-up surveys, which will be in the form of an Amazon.com 
gift card sent electronically or through the mail, depending on participant preference.  We use 
Amazon.com gift cards because they are substantially simpler to disburse from grant funds 
relative to creating personal checks for each participant. A single payment for all completed 
follow-up surveys will be disbursed after the final 12-month survey. 
Healthy controls will be paid $75, or instead can choose to receive a 3D print-out of their brain.  
X. 
CONSENT PROCESS 
Participants will be seated in a private room in CINC and given a paper copy of the consent form.  Each 
study has its own consent form—one for placebo vs. waitlist participants and one for psychotherapy vs. 
waitlist participants.  Additionally, healthy controls have their own consent form.  A member of the 
research team will also give a verbal explanation of the purpose, procedures, risks and benefits of the 
study. Participants will be given a chance to read the consent form and ask any questions.  The informed 
consent form for the MIND data sharing initiative (attached) will also be explained and offered to 
participants, giving them the option of sharing their data with the MIND research network (see also 
below). Participants will also be asked to note whether the study personnel have permission to 
recontact them regarding future studies. Coercion and undue influence will be minimized by reminding 
participants that their participation is voluntary, and that the placebo treatment is unusual and not 
appropriate for everyone.  Regarding EEG collection, the benefits (e.g., contributing to scientific 
research), the additional compensation, and the added burdens (e.g., some gel residue in hair, increased 
time commitment) will be explained to participants, and they will freely choose whether to participate 
in the EEG collection. 

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XI. 
PROCESS TO DOCUMENT CONSENT IN WRITING 
Participants and a member of the research team will both sign the consent form. 
XII. 
PROCEDURES  
Research sites:  All data collection will be conducted at the Center for Innovation and Creativity at 1777 
Exposition Dr., Boulder, CO 80301.  This building houses the Intermountain Neuroimaging Consortium 
MRI facility.  The MRI device is FDA approved for research with human subjects and has all the safety 
inherent in a clinical MRI scanner.  The radio frequency fields conform to guidelines determined by the 
FDA and the FDA has designated MRI scanners to be a non-significant risk device.   The MRI scanning will 
be performed according to the safety and procedural standards of INC. 
 
The placebo treatment will be administered at the Panorama Orthopedics and Spine Center in Golden, 
CO, by Dr. Karen Knight or at the Wardenburg Clinical Translational Research Center (CTRC) with Dr. 
Thomas Flood MD PhD. Psychotherapy will be conducted in rooms at CINC appropriately set up for this 
purpose (i.e., comfortable seating, white-noise machines outside the doors). 
 
The study procedures described below are identical for patients in the psychotherapy study and patients 
in the placebo study.  The only point of divergence is in the treatment delivered. Study procedures for 
healthy controls are described separately later in this section. 
 
Pre-eligibility session verification of pain severity:  Approximately 5 days prior to their scheduled 
eligibility session, patients will be sent a BPI-SF.  If they endorse less than 4/10 average pain intensity 
over the last week, the patient’s eligibility session will be cancelled along with an explanation that based 
on their latest responses they are not eligible.  If patients endorse at least 4/10 pain on this measure, 
their pain report at the eligibility session will not be used as the basis for exclusion (even if they report 
less than 4/10 at that time).  If patients fail to complete this pre-eligibility session BPI-SF, the BPI-SF 
collected at the eligibility session will be used as a basis for inclusion/exclusion.  Our motivation for 
administering this additional online measurement before patients come in to the eligibility session is to 
save patients’ and study time and resources, as the BPI-SF can easily be measured remotely and does 
not require patients to come in in-person only to be quickly told they are not eligible, after completing 
our first survey.   
 
 
Informed consent and eligibility assessment session:  Informed consent will be obtained as described 
above, with participants signing a placebo consent form or a psychotherapy consent form, as 
appropriate.   We will then confirm that a back pain device we have recently developed does elicit back 
pain for the patient.   
 
The back pain device consists of three parts: an inflatable bladder that is placed under the patient’s 
back, a controller which controls inflation level using a pressure regulator, and a pressurized air tank 
(see attachment ‘Back Pain Device.pdf’).  The device design is based on a thumb pressure pain device 
which our lab has used in several studies with no adverse events.  The back pain device is functionally 
equivalent to placing a small pillow under patients’ backs, where the pillow thickness can be dynamically 
controlled.  Pilot studies with N = 10 patients have confirmed that this device is painful for many back 
pain patients, the pain is tolerable, and the pain returns to baseline almost immediately after the 
stimulation ends.  No pilot patient reported any adverse events or lingering pain 1 hour or 1 day after 

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testing.  We have consulted with physicians with expertise in back pain (Co-I Dr. Howard Schubiner and 
collaborator Dr. Rachael Rzasa Lynn), who have confirmed that this device cannot cause damage to 
patients backs, since laying with a pillow under one’s back is fundamentally innocuous though it may be 
painful. The largest bladder we will use will have a 6” diameter.  At any point, if participants indicate 
that pain is above the level they are willing to tolerate, we will discontinue participation.   
 
The bladder controller is programmed such that it cannot inflate beyond 0.25 kg/cm2 units of pressure.  
The bladders cannot burst at this pressure level, which is relatively low (i.e., the bladders still have a fair 
amount of give when pressing on them at this inflation level).  In tests manually inflating the bladder to 
higher levels, the bladder developed a leak only at 7 kg/cm2 (more than 25 times the maximum pressure 
which the controller can administer).  Even at this inflation level, the bladder did not burst, but began to 
slowly leak air from a seam.  Thus, we believe there no risk of bladder bursting. If unexpected external 
pressure were placed on the bladder, it might either a) fail to maintain the desired inflation level, or b) 
develop a small leak along a seam, neither of which pose a risk to participants.  We are using this back 
pain device simply to elicit a pain response. We are not collecting data on its safety or efficacy for 
submission to the FDA. 
 
To calibrate the back pain device for each patient and determine their eligibility, we will ask patients to 
lay on the bladder while it is inflated and deflated to various inflation levels for approximately 12 
minutes.  We will start at the lowest inflation level, so patients can withdraw if desired without 
experiencing higher stimulation levels.  During inflations and deflations, patients will be asked to 
continuously report their pain using a trackball or similar device.  These continuous pain ratings will be 
used for analysis of the EEG data collected during the task for patients who consent to such (see below), 
and for developing models of continuous pain experience elicited by the bladder that will be applied to 
the fMRI data.  Pain report is expected to vary substantially between patients, due to variable baseline 
(pre-existing) levels of pain and to variable responses to the device.  Patients who report no additional 
pain with this device will be deemed ineligible and thanked and paid. 
 
During this back pain calibration task, we will collect electroencephalography (EEG) on participants who 
consent to such. EEG will be recorded using a standard EEG data acquisition device (devices provided by 
Evoke Neuroscience) using an electrode cap (from ANT Neuro) which places electrodes on the scalp over 
the 19 scalp locations of the International 10/20 Electrode Placement System, referenced to linked 
earlobes. Electrodes in the cap are filled with an electrode gel to facilitate connection to the scalp.  Data 
will be sampled at a rate of 200 Hz with 12 bit resolution. Patients will be monitored during EEG 
recording. We will also collect 20 minutes of eyes closed resting state EEG as a reference scan.  EEG 
collection is optional, and patients may decline to do EEG for any reason (e.g., do not want gel in their 
hair, do not have the time available).  Declining EEG will not impact participation in the study in any 
other way.  Compensation provided for the eligibility session will be higher for patients completing EEG, 
since the EEG adds a substantial time demand to the eligibility session. 
 
Participants who consent to EEG will also be asked to complete a “tone tracking” control task.  
Participants will listen to a tone whose volume will fluctuate over approximately 12 minutes.  
Participants will be asked to continuously rate the loudness of the tone.  The tone will never be painfully 
loud; its loudness will remain in the silent to moderately loud range.  The tone frequency will have a 
relatively low frequency, such that it is in the audible range even for people with the loss of high 
frequency hearing.  This task will control for several aspects of the back pain intensity rating task, 
including estimating sensory intensity and the sensorimotor demands of making continuous ratings.  
Participants who do not complete EEG will not be asked to complete this tone tracking task. 

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We will also conduct a pressure pain task to a) determine whether the participant is hyper-sensitive or 
hypo-sensitive to pressure pain stimulations and thus ineligible for our study, and b) to familiarize 
participants with the procedures and device and show them how to terminate the stimulation should 
they need to.  We will administer different levels of pressure pain stimuli in a random order (between 4 
and 7 kg/cm2, max duration = 10 seconds) and ask participants to rate their pain. Inclusion based upon 
hyper- or hypo-sensitivity to painful stimulations will be done using the following criterion: We will 
include participants who report that the stimulations are painful (i.e., not non-painful) but tolerable.  
We will also administer an 8 kg/cm2 pressure stimulation to ensure that the participant can remove his 
or her thumb from the pressure device and knows how to do so (see “RISKS TO PARTICIPANTS” and 
“MANAGEMENT OF RISKS”). We will include participants who can safely remove their thumb from the 
device.  At any point, if participants indicate that pain is above the level they are willing to tolerate, we 
will discontinue participation. 
 
During the consent process, when describing the sound pain task to participants, we will play 
participants the aversive sounds they will hear during fMRI scanning.  This will minimize coercion by 
allowing potential participants to refuse participation prior to granting consent if the sound is 
unacceptable to them. 
 
Eligible patients will be scheduled for the baseline assessment session.  Ineligible patients will be 
thanked, paid, and given a list of treatment referral options.  Eligible patients will also complete several 
questionnaires listed in the table below, under investigation as potential moderators of treatment 
response. 
 
Eligible patients will also be asked to complete a task asking them what feelings they currently have and 
where they feel them in their body (if felt in the body).  Recent research has revealed that many feelings 
have reliable spatial locations in the body (Nummenmaa, Glerean, Hari, & Hietanen, 2013).  Since 
chronic pain patients have altered emotional functioning (Lumley et al., 2011), we hypothesize that they 
may also have altered bodily correlates of emotions or altered ability to locate emotion in their body.  
This “body mapping” task will be completed using a smartphone application, which provides an ideal 
interface for locating feelings in the body (see Figure 2 below).  Participants click an “I feel” button to 
display a list of feelings (i.e., happiness, sadness, pain, fear, stress, etc.), and then can drag a feeling 
bubble to a bodily location (or to a location indicating “not felt in the body”), and then rate the intensity 
of the feeling on a visual analog scale.  
 

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Figure 2.  Screenshot of CliexaEase body mapping smartphone application. 
 
Additionally, the application will ask participants to enter their current medications.  We are interested 
in medications most specifically because of the current opioid crisis, and the potential of the mind-body 
treatments under investigation here to reduce opioid use.  The application has an interface that makes it 
easy for participants to choose their medications from a dropdown list and to choose their dosage from 
commonly prescribed options. 
 
The application, called CliexaEase, is developed by collaborators of ours and is freely available on 
application marketplaces for both Android and iPhone. We will ask participants to download the 
application to their smartphone.  This element of the study is optional:  If participants do not have a 
smartphone, or for any other reason prefer not to do this, this will not impact their study participation in 
any way.   
 
The application will save participants’ random study ID, their body maps of emotions as they report 
them, and their current medication use. This information will be saved to Cliexa servers, from which we 
will download it for our study analysis purposes.  No identifying information will be captured by the app, 
and we will not otherwise provide Cliexa with any identifying information about our participants, and 
Cliexa will not attempt to identify any data (as attested to in the attached data sharing agreement).  We 
will explain this arrangement to participants: that the application developer will receive no identifying 
information, only body maps tagged with random IDs. 
 
Eligible participants will also be asked whether they would like to serve as scheduled back-up 
participants.  Serving as a back-up is optional and has no bearing on any other aspects of their 
participation in the study.  Back-up participants will be asked to arrive at the same time as another 
scheduled participant (the “primary” participant).  If the primary participant fails to show, or is unable to 
be scanned for an unexpected reason (i.e., they got a tattoo since last study contact and did not notify 
the study team), then the back-up participant will be scanned instead.  If the primary participant does 
show and is able to be scanned as expected, the back-up will be thanked, paid $25, and sent home.  This 
determination will be made approximately 1 hour and 10 minutes after the back-up is asked to arrive, 
once the scan for the primary participant is successfully underway.  Participants who would like to serve 

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as back-ups may also have a “primary” scan scheduled for them at a future date (after which they can no 
longer serve as back-ups), or, they may continue serving as a back-up indefinitely, and will have their 
primary scan scheduled only when enrollment nears its end. 
 
3 days before the baseline assessment:  For the 3 days before the baseline assessment, participants will 
be emailed or texted (according to their preference) once per day with a link to the Brief Pain Inventory 
– Short Form (BPI-SF), a primary outcome measure in our study. We conduct this additional 
measurement because previous research suggests that repeated daily measurement of outcome 
measures may be preferable relative to a single measurement collected in the laboratory (R. C. Moore, 
Depp, Wetherell, & Lenze, 2016).  We also repeat this procedure for the 3 days after the baseline 
assessment, yielding a total of 7 pre-treatment measurements of the BPI-SF:  3 days before the baseline 
session, at the baseline session, and 3 days after the baseline session. 
 
Baseline assessment: Each session will begin with welcoming participants, reminding them of the plan 
for that session, and addressing any initial questions.  Participants will then complete self-report 
questionnaires (listed in the table below) at a computer, using the REDCap platform (see Data 
Management below), and will be asked to do a body mapping of their current feelings and their current 
medications using the Cliexa smartphone app as described above.  
 
Participants will then complete a computerized version of a progressive ratio task previously found to be 
altered in chronic pain (Schwartz et al., 2014). In this task, participants can earn a fixed amount of 
money ($1) for a progressively increasing amount of effort. Effort will be operationalized by button 
presses. For the first $1, participants will have to complete 50 button presses. For each additional $1, 
the number of button presses will be increased by a factor of 2.3 (i.e., 115, 265, 608, etc.). Participants 
are free to stop at any time or will be stopped once 20 minutes have elapsed. 
 
Participants will then be escorted to the MRI scanner.  Prior to going into the MRI scanner, the MRI 
technologist on duty will ask participants to remove all jewelry and metal objects from their pockets. 
Participants will be required to change into scrubs to prevent any possible risk from metallic objects or 
decorations in their clothing. 
 
During fMRI scanning, participants will complete several functional MRI tasks.  Tasks completed during 
functional MRI include: 
1. A scan during which participants are asked to rate their ongoing pain intensity using a visual 
analog scale every 30 – 60 seconds.  We will use pillows and blankets to make participants as 
comfortable as possible during this scan to minimize back pain. 
2. A second scan during which participants are asked to rate their ongoing pain intensity using a 
visual analog scale every 30 – 60 seconds.  During this scan, we will elicit back pain using the 
inflation levels that different pain intensities in the eligibility session.  Maximum exposure time 
to the bladder in the scanner will be 15 minutes. 
3. An acute pain and aversive sounds task.  Participants will receive a pseudo-randomized 
sequence of pressure pain stimulations and unpleasant sound stimulations (i.e., the sound of a 
knife moving across glass).  Pressure stimulations will be administered to the left thumbnail.  
Pressure pain stimulations will be administered using a pressure pain device (see attachment 
“Pressure pain device”) and will be within the safe range based on our pilot data and previous 
studies (see attachments “Pressure pain pilot study results” and “Pressure pain stimulation 
guideline”).  Aversive sounds will serve as a control condition for non-pain related negative 
affect.  These aversive sounds will be taken from a widely used standardized database of 

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unpleasant sounds, the International Affective Digital Sounds (IADS) database, and will be mildly 
to moderately unpleasant. Another ongoing study (IRB protocol #15-0483) has run over 50 
participants to date with both the thumb pressure device and the aversive sounds with no 
adverse events.  Following stimulations, participants will be asked to rate the intensity and/or 
unpleasantness of the pain or sound.  
 
We will also collect heart rate and respiration during the fMRI scans using MRI-compatible devices 
routinely used at CINC.  These physiological measures will be used for de-noising the fMRI data. 
 
A venous blood sample with be collected at this session and again at the post-treatment assessment 
scan. The blood sample will consist of an upper extremity blood draw via standard venipuncture 
technique (https://www.ncbi.nlm.nih.gov/books/NBK138650/pdf/Bookshelf_NBK138650.pdf, 2017). 8cc 
of blood will be collected per draw (16cc total/subject over the entire study). All study personnel 
performing the blood draws with be trained by Dr. Thomas Flood in accordance with the ‘WHO 
guidelines on drawing blood: best practices in phlebotomy’ 
(https://www.ncbi.nlm.nih.gov/books/NBK138650/pdf/Bookshelf_NBK138650.pdf, 2017).  Dr. Flood is a 
senior radiology resident with the University of Colorado Diagnostic Radiology Residency (post-graduate 
year 5) with clinical training in numerous medical procedures, including blood draws.  Since Colorado 
state law does not require a certification for performing blood draws, the WHO guidelines will serve as 
our standards for compliance. Areas of phlebotomy training will include: anatomy of acceptable sites to 
be used for venous sampling, infection prevention and control, protection of the study subject, 
protection of the study personnel working with blood samples, types and proper use of equipment, 
practice obtaining blood samples, adverse events/occupational exposure and management, waste 
management (including disposal of sharps and biologic waste, and procedures for spillage/breakage), 
and proper labelling, handling, and transportation of samples. All study personnel will demonstrate 
appropriate skill and mastery of the training content prior to performing venous blood draws on study 
subjects. The risks of blood draws via standard venipuncture technique are minimal and include pain, 
bruising at the venipuncture site, redness and swelling of the vein and infection, and a rare risk of 
vagovasal response.   
 
If there is a contraindication to performing the blood draw (i.e., cutaneous infection or scarring at the 
site of sampling, difficulty locating a vein, excessive fear/phobia of needles that the subject had not 
previously reported during informed consent), a blood spot will be collected instead. The blood spot will 
be collected with a finger stick collection device sold by Spot On Sciences HemaSpotTM device.  The 
device draws 2 -3 drops of blood from the fingertip, is mildly painful, and has minimal associated risks. 
All assessment sessions for a given participant will be scheduled at approximately the same time of day, 
because of the influence of circadian rhythm on biological measures.  Blood samples will be used to 
measure the immune markers IL-1, IL-6, and IL-10. 
 
Participants will also complete a task designed to measure willingness to experience pain, which has 
been identified as a maintenance factor in chronic back pain.  Participants will be given a $10 
endowment for this task, which they can keep or spend as they choose.  They will place bids in a series 
of Becker-DeGroot-Marschak (BDM) (Becker, Degroot, & Marschak, 1964) auctions on how much not 
experiencing pain is worth to them.  Participants will be asked to bid a dollar amount ($0 - $10, in $1 
increments) on how much they would like to not experience pain of X minutes.  The duration of pain (X 
minutes) will range from 0 to 10 minutes and will be randomly varied across trials.  After the last trial, 
one of the trials will be randomly chosen to be implemented as a BDM auction.  A random number will 
be chosen.  If the random number is larger than the participant’s bid, the participant will keep the full 

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$10 and experiences the pain indicated on that trial.  If the random number is smaller than the 
participant’s bid, the participant will not experience any pain.  Instead, they must pay back the amount 
bid and keep the remainder of the endowment.  The optimal strategy in such auctions is to bid the true 
value of not experiencing pain for X minutes, and participants will be informed of this.  We will also 
carefully explain this task to participants and provide an opportunity for questions, given the potentially 
confusing nature of this auction.  Similar BDM auctions for experiencing pain have been previously 
conducted (Vlaev et al., 2012; Vlaev, Seymour, Dolan, & Chater, 2009; Winston, Vlaev, Seymour, Chater, 
& Dolan, 2014).  But here, we will do this with chronic pain.  The pain administered will be the bladder 
inflation level eliciting approximately 5/10 intensity back pain. 
 
 
Randomization:  At the end of the baseline session, we will randomize patients to treatment or wait-list.  
Randomization will be stratified by baseline pain severity, age, gender, and opioid use.  Patients will be 
randomized at a 2:1 ratio of treatment to waitlist, as described in the Study Design.  Patients in the 
placebo study randomized to treatment will receive the placebo injection.  Patients in the 
psychotherapy study randomized to treatment will start psychotherapy.  
 
For 3 days after the baseline assessment:  For the 3 days after the baseline assessment, participants will 
be emailed or texted (according to their preference) once per day with a link to the Brief Pain Inventory 
– Short Form (BPI-SF).  
 
Treatment:  Treatment details are described separately for each study below. 
 
Treatment (placebo study):  The placebo treatment session will be with Dr. Karen Knight at the 
Panorama Orthopedics and Spine Center in Golden, CO or with Dr. Thomas Flood MD PhD at the 
Wardenburg Clinical Translational Research Center (CTRC).  Dr. Knight is a physical medicine and 
rehabilitation specialist with broad experience in both rehabilitative medicine and pain management.  
She is board certified in Physical Medicine & Rehabilitation with additional certifications in Sports 
Medicine, Integrative Medicine and Pain Medicine.  She has received several awards and honors for her 
clinical work, including  being listed as a 5280 Top Doc several times, receiving the National Bernard 
Baruch Medal, and the Vitals Patients’ Choice Award.  She has over a decade of experience in 
administering therapeutic injections for pain management. Dr. Thomas Flood is a senior radiology 
resident with the University of Colorado Diagnostic Radiology Residency (post-graduate year 5). Dr. 
Flood has clinical training in numerous medical procedures, including the proper administration of 
subcutaneous injections. Dr. Flood has extensive research training with numerous peer-reviewed first-
author publications in basic, translational, and clinical research. Dr. Flood was awarded a competitive 
grant from the Radiological Society of North American to carry out the research outlined in this 
proposal.  Dr. Flood’s malpractice insurance covers his practice at the CTRC.  An IAA has been arranged 
for COMIRB (which covers Dr. Flood) to cede to the CU Boulder IRB to cover Dr. Flood’s engagement in 
this research. 
 
To schedule patients, we will send a secure email (from University of Colorado email servers to a secure 
email server at the Panorama clinic) to the clinic front desk with demographic and contact information 
of patients who are ready to be scheduled for treatment (demographic information is required for 
patients to be entered into the clinic’s computer system).  All Panorama clinic staff are HIPPA trained 
and compliant and will handle participants’ data as protected health information. During the informed 
consent process, patients will sign a HIPPA form allowing the release of PHI to the clinic.  The clinic will 

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then contact patients and schedule them. Dr. Flood is a co-investigator on the current proposal and will 
schedule subjects at the CTRC, according to HIPPA compliant procedures. 
 
The open-label placebo treatment we will use is based on past open-label placebo trials (Kam-Hansen et 
al., 2014; Kaptchuk et al., 2010; Kelley et al., 2012).  Prior to treatment administration, patients will view 
a brief (~3 min) video summarizing scientific findings regarding the therapeutic power of placebo 
treatments.  The video will describe established findings regarding placebo and suggest that placebos 
may still work even when patients know the treatment is a placebo.  The placebo treatment will consist 
of a subcutaneous injection of saline into the participant’s lower back according to the following 
procedure. The physician will wash their hands (either with soap and water or an alcohol-based hand 
rub) before entering and leaving the procedure room. The placebo injection procedure will be described 
to the participant and verbal acknowledgment of understanding of the procedure will be obtained; the 
opportunity to ask questions and obtain clarifying information will be given. The participant will also be 
informed of the procedural steps (as described below), concurrently as they occur. Next, the participant 
will be asked to lay prone on the examining table. The participant’s lower back will be exposed, with the 
use of proper draping technique. The participant’s exposed skin will be examined for signs of any 
dermatologic abnormality, which may be a contraindication to the injection (as detailed below). The 
participant will be asked to point to the area of localized pain. The location of the subcutaneous 
injection will be selected in proximity to the area of subjective pain within the soft tissues of the lower 
back (lateral to the midline). Prior to administering the injection, the physician will again wash their 
hands (with soap and water or an alcohol-based hand rub) and put on non-sterile nitrile examination 
gloves. Additional supplies include: a 10 ml disposable single-use vial of sterile, nonpyrogenic, isotonic, 
medical grade sodium chloride and water solution (0.9% sodium chloride; the solution will not contain 
any bacteriostatic/antimicrobial agents, added buffer, or preservatives), a sterile deposable syringe (1 
ml) and needle (27 gauge; ½ -1 inch in length), a sterile 2x2 inch gauze pad, alcohol pads, a “sharps” 
container for syringe and needle disposal, and a Band-Aid. The vial of saline will be opened and the top 
will be cleansed with an alcohol pad. The syringe/needle will be opened and 1 ml of saline will be 
withdrawn from the vial to fill the syringe; air bubbles will be removed. The participant’s skin (at the 
area of injection) will be cleansed with an alcohol pad and allowed to air dry. Then the needle will be 
introduced into the subcutaneous tissue of the lower back and 1ml of saline will be injected (using a 
slow steady rate of injection). The needle will be removed, sterile gauze will be gently applied to the site 
of injection, and then a Band-Aid will be placed. The needle/syringe will be disposed of in an appropriate 
“sharps” container located within the procedure room. Contraindications to the procedure include: an 
excessive fear/phobia of needles, an inability to arrive at the treatment site on their own, or a significant 
cutaneous abnormality that is located within proximity to the lower back injection site, including signs of 
infection (erythema, warmth, swelling, induration), an active wound, scar tissue, or other significant 
dermatologic abnormality. Following the treatment, the Panorama clinic will send us a secure email 
saying patient with initials YZ (for example) got the treatment on X date. 
 
Treatment (psychotherapy study): Psychotherapy will consist of an initial medical history session with 
Co-I Schubiner, a brief intake phone call with lead psychotherapist Alan Gordon, and twice weekly 50 
minute psychotherapy sessions for 4 weeks with a therapist.   
 
The purpose of the initial medical history session is to help evaluate the likelihood that the patient’s 
back pain is caused by structural conditions in the back.  No patients will be excluded as a result of this 
evaluation.  Patients will send Dr. Schubiner any medical or radiological reports they have available using 
secure fax or secure email provided by Dr. Schubiner’s hospital. Patients will complete a HIPAA 
authorization during the informed consent process to cover this sharing of PHI.  Dr. Schubiner will then 

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speak with patients for a 1 hour session in which he collects their medical history and discusses different 
possible causes of their back pain with them.  This session will be conducted by phone or by HIPAA-
compliant videoconferencing technology arranged in consultation with the OIT team at Dr. Schubiner’s 
hospital. Patients can conduct this session at any location they prefer, and will be offered to do it from a 
private room in CINC if they would like.  Dr. Schubiner has conducted hundreds of such assessments in 
the context of his clinical practice and in previous research trials (Hsu et al., 2010).  He will not provide 
patients with a formal diagnosis but with a diagnostic impression of the causes of their pain according to 
his clinical judgment.  Dr. Schubiner will prepare a brief report regarding his impressions for each patient 
that will be stored in REDCap and will be accessible by therapists.  Dr. Schubiner is licensed to practice 
medicine in Colorado (pro bono license). 
 
Alan Gordon (lead psychotherapist) will then have a brief phone call with the patient (~10 minutes) 
orienting them to the psychotherapeutic approach and scheduling their first psychotherapy session. 
 
Psychotherapists in this trial will be from the Pain Psychology Center (www.painpsychologycenter.com), 
a well-established private practice clinic in Los Angeles with expertise in psychotherapy for CBP.  
Therapists will come to Boulder to see patients for the study.  Alan Gordon, LCSW and executive director 
of the Pain Psychology Center, will supervise all therapists in weekly supervision and case consultation 
meetings.  All therapists will be licensed to practice in Colorado and will be experienced in the treatment 
of CBP.  The psychotherapy incorporates techniques from established modalities with known efficacy, 
including cognitive behavioral therapy (CBT) and acceptance-based approaches.  Additionally, leveraging 
the medical history report, therapists will help patients consider whether their back pain is caused by 
structural conditions in the back, and if it is not, whether the pain truly signals damage to the back.  
While this component is present to some in existing psychotherapies, the emphasis on it here presents a 
novelty of our psychotherapeutic approach.  The therapists seeing patients include:  Alan Gordon, Daniel 
Lyman, Jonathan Ashar, Christie Uipi, and Ed Walton.  Dr. Schubiner will be available to therapists for 
consultation in case of back-related medical questions.  Dr. Dimidjian will also provide consultation as 
needed, given her extensive experience in psychotherapy research trials.   
 
Psychotherapy sessions will be video-taped, for later coding of therapist and client behaviors, as is 
standard procedure in psychotherapy trials. Recent advances in affective computing have allowed the 
automatic detection of emotional experience from facial expression, opening new methods for probing 
affective experience during psychotherapy.  These tools require capturing facial features that also make 
subjects identifiable from the videos. For patients who consent, excerpts from videos may be shown for 
educational purposes (i.e., at conference presentations).  At any point, patients may ask the therapist to 
stop the video and the therapist will comply.  Patients will be told at the outset that they can request 
this at any time. 
 
In the rare event that a therapist must unexpectedly leave Boulder or is unable to continue in-person 
treatment, the patient will be transferred to a different therapist.  However, if the patient is near the 
end of treatment, the patient and therapist may agree to conduct the last sessions over phone or secure 
videoconferencing instead.  The patient will be given the option of transferring therapists or continuing 
with the same therapist via secure videoconferencing. 
 
Brief weekly surveys during the treatment phase (this and following procedures again apply to all 
patients in both studies):  All patients will be sent a weekly questionnaire between treatment initiation 
and the post-treatment assessment session.  For waitlisted participants, questionnaires will start 

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approximately one week after the baseline assessment session.  Participants will be emailed or texted 
(according to their preference) a few brief surveys as listed in the table below.   
 
Daily surveys for 3 days before post-treatment session:  As at the baseline assessment, for 3 days 
before the post-treatment assessment, participants will be emailed or texted (according to their 
preference) once per day with a link to the to the Brief Pain Inventory – Short Form (BPI-SF).  
 
Post-treatment assessment:  About 4 weeks after initiating treatment (i.e., the medical history session 
for psychotherapy patients or receiving the injection for placebo patients), all patients will return to 
complete a second assessment. Waitlisted patients will return about a month after the baseline session.  
This session is identical to the baseline assessment, but with two additional questionnaires administered 
(the PGIC and the treatment satisfaction questionnaire).   
 
Patients will then be asked if they would be willing to speak on camera about their experiences with the 
treatment, in their own words.  Qualitative measures such as this can detect important information that 
quantitative measures may completely miss, and they can offer a different view on the effect of 
treatment (i.e., Allen, Bromley, Kuyken, & Sonnenberg, 2009; K. M. Moore & Martin, 2015).  We collect 
this qualitative data to supplement the many quantitative measures already being collected.  If patients 
agree, a member of the research team will conduct a semi-structured interview asking about their 
history of back pain, their sense of whether the treatment was of benefit, and what they think was most 
and least helpful about the treatment they received.  The interview will be video recorded in a study 
testing room affording privacy to the patient.  The interview is optional and declining will not impact 
study participation in any way.  It will take 10 – 15 minutes, and we will offer participants some snacks 
and drinks prior to the interview, as it is at the end of a 3-hour session and they may appreciate the 
refreshments.  Participants who agree to the interview will be asked to indicate allowed uses of the 
recording on a form (see attached).  They will be administered this form immediately prior to the 
interview, rather than during the initial consent process, so that they can make a decision better 
informed by their study experience thus far.  Participants who completed the study prior to the addition 
of this interview to the study protocol will be invited to come in for this interview.  They will be paid $30 
for doing so.  Declining to come in for the interview will not impact their participation in the study in any 
other way. 
 
Daily surveys for 3 days after post-treatment session: For 3 days after the post-treatment assessment, 
participants will be emailed or texted (according to their preference) once per day with a link to the to 
the Brief Pain Inventory – Short Form (BPI-SF). This yields a total of 7 post-treatment measurements of 
the BPI-SF:  3 days before the post-treatment session, at the session, and 3 days after the post-
treatment session. 
 
Offering treatment to wait-listed patients:  Wait-listed patients in the placebo injection study will be 
offered the opportunity to receive the placebo treatment (optional).  Waitlisted participants in the 
psychotherapy study will be given a copy of Dr. Schubiner’s book and free access to his online self-help 
program (optional to accept these). 
 
Follow-up:  At months 1, 2, 3, 6, and 12 after their final assessment, all patients will be emailed an 
online survey including the self-report outcome measures (listed in table below), along with a request to 
open the CliexaEase application on their smartphone and complete a body mapping of their current 
feelings.  We will attempt up to 4 total contact attempts via phone or email over a maximum of 3 weeks 
to patients who do not respond to the survey. 

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Healthy Controls 
 
Healthy controls will be recruited through the Wager lab general screening protocol  (approved IRB 
protocol #10-0243).  This protocol covers the recruitment and screening of healthy subjects for pain 
fMRI experiments, which describes the experience of healthy controls in the current study.  Participants 
recruited through this protocol complete an online eligibility pre-screening REDCap survey regarding 
MRI eligibility and basic demographic and contact information.   
 
Participants who are likely eligible based on this form will be called.  The procedures for healthy controls 
in our study will be briefly explained to them. We will describe the general purpose of the study as 
investigating the brain bases of chronic back pain, and explain to these participants that they will serve 
as a healthy control group for back pain patients.   
 
If participants are interested, we will ask them some additional questions about inclusion/exclusion 
criteria that are not covered by the general lab screening protocol.  The experimenter will read a list of 
yes/no questions, and instruct the participant to say after the last question whether the answer was 
‘yes’ to any of the questions that had been read.  This procedure will help protect participants’ privacy in 
leaving unclear the exact reason for exclusion.  The questions are:  
• 
Have you ever had back pain lasting more than 2 weeks? 
• 
Have you ever been diagnosed with a chronic pain condition? 
• 
Have you ever been diagnosed with schizophrenia, multiple personality disorder, or dissociative 
identity disorder? 
• 
Have you ever had a metastasizing cancers—a cancer of the breast, thyroid, lung, kidney, 
prostate or blood cancer? 
• 
Have you ever had a stroke, brain surgery, or brain tumor? 
• 
Have you ever been diagnosed with rheumatoid arthritis, polymyalgia rheumatica, scleroderma, 
Lupus, or polymyositis? 
• 
Have you had an unexplained, unintended weight loss of 20 lbs. or more in the past year? 
• 
Do you use intravenous drugs? 
• 
Do you regularly use of an immunosuppressant drug, such as steroids? 
• 
Do you have difficulty controlling bowel or bladder function? 
 
We are also in the process of submitting an amendment to the Wager lab general screening form 
protocol to ask the above questions so we do not need to do so by phone.  Once this amendment is 
approved and participants and completing the updated screening form, we will no longer need to ask 
these questions by phone. 
 
Participants who are interested and likely eligible will be scheduled for an fMRI session.  This session is 
similar to the eligibility and baseline assessment sessions for patients described above.  It consists of the 
following procedures: 
1. Informed consent 
2. The thumb pressure pain eligibility task, described above, to ensure that tolerable pain is 
elicited.  If the device is not painful or is intolerably painful, participants will be excluded.  Based 
on previous experience with this device, very few participants will be excluded for this reason.  

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3. Back pain device familiarization.  This will follow the procedure described above for patients, in 
which we expose participants to different inflation levels and ask them to provide continuous 
ratings of pain experience.  Unlike patients, controls will not be excluded based on pain report 
or lack thereof.  The device is not expected to cause more than mild back pain for healthy 
controls, as pilot subjects  with no history of back pain (n = 5) reported no pain or mild pain at 
the maximum inflation level.  EEG will not be collected on healthy controls during this task, as it 
is for patients only, and healthy controls will not complete the tone tracking control task. 
4. Questionnaires at a computer, using REDCap.  Questionnaires are listed below. 
5. Participants will be asked to download the CliexaEase application and complete a body mapping 
of their current feelings (optional) and to list current medications. 
6. fMRI scanning session identical to that completed by patients, described above.   
7. The progressive ratio task. (Healthy controls will not do the willingness to experience pain task, 
because the back pain device will not be painful for most of these participants.) 
8. A single blood sample will be collected: a serum draw, or if contraindicated for the reasons listed 
above, a blood spot. 
9. Participants will be thanked and paid. 
 
Healthy control participants who are interested and eligible will also be asked whether they would like 
to serve as scheduled back-up participants.  Serving as a back-up is optional and has no bearing on any 
other aspects of their participation in the study.  Back-up participants will be asked to arrive at the same 
time as another scheduled participant (the “primary” participant).  If the primary participant fails to 
show, or is unable to be scanned for an unexpected reason (i.e., they got a tattoo since last study 
contact and did not notify the study team), then the back-up participant will be scanned instead.  If the 
primary participant does show and is able to be scanned as expected, the back-up will be thanked, paid 
$25, and sent home.  This determination will be made approximately 1 hour and 10 minutes after the 
back-up is asked to arrive, once the scan for the primary participant is successfully underway.  
Participants who would like to serve as back-ups may also have a “primary” scan scheduled for them at a 
future date (after which they can no longer serve as back-ups), or, they may continue serving as a back-
up indefinitely, and will have their primary scan scheduled only when enrollment nears its end. 
 
 
 
Name of instrument/tool/procedure 
Purpose (i.e. what data is 
being collected? 
Time to Complete 
Positive and Negative Affect Scale 
short form (PANAS-SF) (“panas 10” 
file) 
Secondary outcome 
measure 
1 minute 
Brief Pain Inventory—short form 
(BPI-SF) 
Co-primary outcome 
measure and 
administered weekly 
during treatment 
1 minute 
Oswestry Low Back Pain Disability 
Questionnaire (OLBPD) 
Co-primary outcome 
measure 
4 minutes 
PROMIS short forms: anger (5 
items), sleep disturbance (8 items), 
Secondary outcome 
measure and 
2 minutes altogether 

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anxiety (8 items) and depression (8 
items) 
administered weekly 
during treatment 
Tampa Scale of Kinesiophobia (TSK) 
Secondary outcome 
measure and 
administered weekly 
during treatment 
1 minute 
Survey of Pain Attitudes Short Form, 
Emotion subscale (SOPA-Emo) 
Secondary outcome 
measure and 
administered weekly 
during treatment 
< 1 minute 
Patient Global Impression of Change 
(PGIC) scale 
 
Post-treatment-only 
outcome measure 
1 minute 
Treatment satisfaction 
questionnaire 
 
Post-treatment-only 
outcome measure 
1 minute 
Semi-structured interview about 
treatment experience 
Post-treatment-only 
outcome measure 
10 – 15 minutes 
Pain Catastrophizing Questionnaire 
(PCS) 
Secondary outcome 
measure 
2 minutes 
Fear of Pain Questionnaire 
Potential moderator 
3 minutes 
General Self-Efficacy Scale (GES) 
Potential moderator 
of treatment effect 
2 minutes 
Mindful Attention Awareness Scale 
(MAAS) 
Potential moderator of 
treatment effect 
2 minutes 
Emotion Regulation Questionnaire 
(ERQ) 
Potential moderator 
of treatment effect 
2 minutes 
Life Orientation Test-Revised (LOT-
R) 
Potential moderator 
of treatment effect 
1 minutes 
Timeline Follow-Back Measure for 
alcohol and drug use (TLFB) 
Secondary outcome 
measure 
8 minutes 
Treatment history form, asking how 
effective previous injection 
treatments have been for patients’ 
CBP  
Potential moderator 
of treatment effect 
1 minutes 
Demographic information 
Potential moderator 
of treatment effect 
1 minutes 
Adverse Childhood Experiences 
questionnaire (ACE) 
Potential moderator 
of treatment effect 
2 minutes 
BMQ-Specific modified 
Potential moderator 
of treatment effect 
1 minute 
 
 
 
MRI 
Outcome measure 
1 hour 
Dried blood spot 
Outcome measure 
5 minutes 
Baseline and post-treatment daily 
surveys  
To better measure 
treatment effect on 
primary clinical 
outcomes 
1 minute/day 

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Progressive ratio button pressing 
task 
Outcome measure 
0 – 20 minutes 
maximum, estimated 
mean of 5 minutes 
Willingness to experience pain task 
Potential moderator 
and outcome measure 
5  – 15 minutes, 
estimated mean of 
10 minutes 
Pressure pain eligibility task 
Eligibility measure 
10 minutes 
Back pain elicitation eligibility task 
Eligibility measure 
10 minutes 
Emotion body mapping and 
medication use, collected via 
smartphone application 
Potential moderator 
and outcome measure 
5 minutes 
EEG 
Potential brain 
marker of pain 
intensity 
50 minutes 
 
 
The total time commitment for a subject is 8 hours over 1.5 – 2 months (not including follow up surveys 
which may add 1 hour over the following year).  Psychotherapy subjects will have an additional 7 – 9 
hour time commitment.   
 
 
 
Visit # 
Procedures/Tools 
Location 
How much time the 
visit will take 
Online pre-
screening 
• 
Online eligibility pre-
screening form  
online 
15 minutes 
Pre-eligibility 
session online 
screen 
• 
BPI-SF 
online 
1 minute 
Eligibility 
session 
• 
Informed consent 
• 
LOT-R 
• 
ERQ 
• 
GES 
• 
TSK 
• 
SOPA-Emo 
• 
MAAS 
• 
TLFB 
• 
BPI-SF 
• 
OLBPD 
• 
IPQ 
• 
Fear of Pain 
Questionnaire 
• 
PCS 
• 
PANAS-10 
• 
ACE 
• 
BMQ-Specific 
modified  
CINC 
1.5 hours without 
EEG, 2.5 hours 
with EEG 

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• 
Treatment history 
form  
• 
Demographic 
information 
• 
Pressure pain 
eligibility task 
• 
Back pain elicitation 
eligibility task 
• 
Emotion body 
mapping and 
medication use 
• 
EEG (optional) 
Baseline 
assessment 
session 
• 
MRI session 
• 
Blood sample 
• 
Positive and 
Negative Affect 
Scale short form 
(PANAS-SF) 
(“panas 10” file) 
• 
PROMIS short 
forms: anger, 
sleep 
disturbance, 
anxiety, and 
depression 
• 
BPI-SF 
• 
OLBPD 
• 
TLFB 
• 
TSK 
• 
SOPA-Emo 
• 
Fear of Pain 
Questionnaire 
• 
BMQ-Specific 
modified 
• 
Pain 
Catastrophizing 
Questionnaire 
(PCS) 
• 
PROMIS short 
forms: anger, 
sleep 
disturbance, 
anxiety, and 
depression 
• 
Emotion body 
mapping and 
medication use 
CINC 
3 hours 

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• 
Progressive ratio 
button pressing 
task 
• 
Willingness to 
experience pain 
task 
Placebo 
treatment 
session 
• 
Subcutaneous 
injection 
Panorama 
Orthopedics and 
Spine Center 
30 minutes 
Psychotherapy 
treatment 
sessions 
• 
Initial medical 
history followed 
by twice weekly 
psychotherapy 
sessions for 4 
weeks (8 
sessions max) 
CINC 
1 hour per session 
= 7 – 9 hours total, 
depending on how 
many sessions a 
patient attends 
Weekly surveys 
during 
treatment 
phase 
• 
BPI-SF 
• 
TSK 
• 
SOPA-Emo 
• 
PROMIS short 
forms: anger, 
sleep 
disturbance, 
anxiety, and 
depression 
At home 
10 minutes 

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Post-treatment 
assessment 
session 
• 
MRI session 
• 
Blood sample 
• 
Positive and 
Negative Affect 
Scale short form 
(PANAS-SF) 
(“panas 10” file) 
• 
BPI-SF 
• 
OLBPD 
• 
TLFB 
• 
TSK 
• 
SOPA-Emo 
• 
Fear of Pain 
Questionnaire 
• 
Pain 
Catastrophizing 
Questionnaire 
(PCS) 
• 
PROMIS short 
forms: anger, 
sleep 
disturbance, 
anxiety, and 
depression 
• 
Patient Global 
Impression of 
Change (PGIC) 
scale 
• 
Treatment 
satisfaction 
questionnaire 
• 
Emotion body 
mapping and 
medication use 
• 
Progressive ratio 
button pressing 
task 
• 
Willingness to 
experience pain 
task 
• 
Interview 
CINC 
3 hours, or 
3 hours 15 
minutes if agree to 
the interview 
6-month follow-
up online survey 
• 
Positive and 
Negative Affect 
Scale short form 
(PANAS-SF) 
(“panas 10” file) 
• 
BPI-SF 
 
10 – 15 minutes 

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• 
OLBPD 
• 
PROMIS short 
forms: anger, 
sleep 
disturbance, 
anxiety, and 
depression 
• 
TSK 
• 
Patient Global 
Impression of 
Change (PGIC) 
scale 
• 
Treatment 
satisfaction 
questionnaire 
• 
Emotion body 
mapping and 
medication use 
Session for 
healthy controls 
• 
Informed consent 
• 
Demographic 
information 
• 
Pressure pain 
eligibility task 
• 
Back pain task 
 
3 hours 
 
• 
Positive and 
Negative Affect 
Scale short form 
(PANAS-SF) 
(“panas 10” file) 
• 
BPI-SF 
• 
OLBPD 
• 
Pain 
Catastrophizing 
Questionnaire 
(PCS) 
• 
PROMIS short 
forms: anger, 
sleep 
disturbance, and 
depression 
• 
LOT-R 
• 
ERQ 
• 
Fear of Pain 
Questionnaire 
• 
MAAS 
• 
GES 
• 
MRI session 
 
 

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• 
Progressive ratio 
button pressing 
task 
• 
Blood sample 
XIII. 
SPECIMEN MANAGEMENT 
Blood samples will be stored in a locked cabinet on site (CINC) in a facility designated specifically for 
storing biological specimens or within a secure -80C research grade freezer at the CU Boulder main 
campus. All stored data will be coded with a randomly generated number, and the master list linking the 
numbers to participants’ names will be stored on a password protected server.  At study closure, all 
biological specimens will be destroyed.  DNA will not be extracted from these specimens. 
XIV. 
DATA MANAGEMENT 
According to HRP-111, this is a low risk (Level 1) study. 
 
Strict standards of confidentiality will be maintained.  All self-report data will be collected with the 
REDCap platform managed by UC Denver.  REDCap is a secure, widely used data collection tool.  Only 
research team members will have access to the REDCap data platform.  The only pen-and-paper data 
that will be collected is the informed consent form.  This will be stored in a locked file cabinet in a locked 
room at CINC.  Identifying information will be collected during the online pre-screen, which asks for 
participants’ names, phone numbers, and email addresses.  After study completion, this information will 
be removed from the REDCap database, permanently de-identifying the REDCap data. 
 
The only exception to the above are the measures of emotion body mapping and current 
medications collected by the Cliexa smartphone application. This data will be tagged only with random 
IDs and does not constitute PHI.  Cliexa will periodically send the data to the research team, who will 
save it on secure, password-protected servers.  Cliexa will never receive any identifying information and 
will make no attempts to re-identify the data.    
 
MRI data will be stored according to standard INC data management procedures. MRI images and 
psychotherapy session videos will be housed on a password protected CU Boulder server. Metadata 
(name and contact information) will be entered into the COINS database by study personnel. Each 
COINS entry will receive a unique research subject identifier. This code will be associated with the 
images. A copy of the MRI images will be sent to the Mind Research Network. No identifying information 
is included in the images. 
 
EEG data will be collected using an Evoke Neuroscience EEG headset.  The headset wirelessly 
transmits data back to the company’s servers, tagged only with a random identifier.  The data is then 
available for download by the research team.  The data will also be available for download by our 
collaborators at PainQX, Inc.  who may use it to develop EEG markers of pain intensity.  For this purpose, 
we will share with PainQX measures of self-reported chronic pain intensity, as well as relevant 
covariates include depression, anxiety, age, and gender.  We will not share identifying information with 
PainQX, and PainQX will make no effort to identify the data, as attested to in the attached form.   
 

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Medical and radiological reports sent to Dr. Schubiner will be stored on a password protected server 
or a locked file cabinet administered by his hospital accessible only to him. 
 
The video recordings will all be collected on one camera which will be stored in a locked room 
between interviews.  The recordings will be regularly downloaded from the camera, transferred to a 
secure, password-protected server accessible only to the research team, and deleted from the camera. 
XV. 
WITHDRAWAL OF PARTICIPANTS 
We may withdraw participants from the study if: we learn that they added, changed, or stopped any 
concurrent treatment for their pain (for example, undergoing back surgery mid-study); participants’ 
back pain dramatically worsens and we judge they need more intensive treatment than that provided in 
this study. 
 
Withdrawn subjects will have no further data collected from them, and there will be no follow up 
contact with them.  If they request it in writing, we will delete all previously collected data linked to 
them.  They will be replaced with new subjects. 
XVI. 
RISKS TO PARTICIPANTS 
Subcutaneous injection:  subcutaneous  injection has minimal risk of adverse events when delivered 
in accordance with guidelines (Annersten & Willman, 2005; 
https://www.cc.nih.gov/ccc/patient_education/pepubs/subq.pdf, 2017).  Adverse events include 
bruising or hematoma at the site of injection, typically resolving within a few days (Annersten & 
Willman, 2005), and in very rare cases, infection.  Risks will be minimized by following the injection 
procedure, (as detailed above; see the “Treatment (placebo study)” subsection within the “Research 
Design and Methods” section), and by not administering the lower back subcutaneous injection within 
proximity to a significant cutaneous abnormality, including signs of infection (erythema, warmth, 
swelling, induration), an active wound, scar tissue, or other significant dermatologic abnormality. 
Subcutaneous injections are performed as part of routine medical appointments.  They are considered 
safe even for at-home self-administration (i.e., insulin for diabetics), although this will not be done in 
this study.  
 
MRI:  The risks of MRI are: 
• 
The MRI may cause discomfort due to scanner noise.  
• 
There may be some discomfort from lying still and in one position for a long time. 
• 
Peripheral nerve stimulation (PNS/tingling). At sufficient exposure levels, peripheral nerve 
stimulation is perceptible as “tingling” or “tapping” sensations. PNS symptoms will usually 
subside shortly after the scan is completed. 
• 
Participants may feel nervousness or feelings of claustrophobia. 
• 
MRI may pose risks to fetuses, we thus exclude potentially pregnant women.   
 
While the images are taken for research purposes, participants will be notified should an anomaly of 
clinical importance be observed, as is standard practice for INC/MRN images. 
 

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Injury due to pressure pain device malfunction: There is a very slight risk to the participant in case of 
pressure pain device malfunction. We have tested the device on 50 participants in an ongoing study and 
12 in-lab participants (see attachment “Pressure pain pilot”) without any incidents. In addition, we 
systematically tested if participants could readily remove their thumb from the device under high-
pressure stimulation (e.g., 8 kg/cm^2) and specifically when pressure was experienced as too high to 
tolerate for an extended period.  Eleven participants finished the test, and all were able to remove their 
thumb from the device. One participant terminated the experiment after the first few trials due to 
hypersensitivity to pressure. We also asked participants whether they experienced any long-term harmful 
effects of pressure pain. The survey showed that there was no remaining mark on the thumb after 3 hours 
for all participants who finished the test, and minimal tenderness was found after three hours. In addition, 
all participants who finished the test had no remaining sensation after three hours. The participant who 
discontinued the pilot experiment early reported discomfort for several hours after the experiment, but 
it disappeared within 24 hours.  In the ongoing study (current N = 50), no adverse events have been 
reported.  Therefore, we expect that most participants will experience no risk due to the pressure pain 
device.  
 
Back pain device:  The inflatable bladder can cause pain and psychological discomfort.  The levels of 
pain elicited will be within participants’ tolerable level and will not cause any damage to participants’ 
backs.  The back pain elicited will be similar to what they feel during the course of daily life.  The bladder 
cannot inflate beyond a 6” diameter.  Additionally, the device has a low maximum pressure (0.25 
kg/cm2) beyond which it will not inflate, so the bladder will not burst from pressure. 
 
Risk of psychotherapy:  Psychotherapy contains inherent risks (Dimidjian & Hollon, 2010).  The 
therapy being tested here, while novel in some respects, is closely related to existing cognitive-
behavioral and acceptance-based therapies that are widely used in research and practice.  While 
systematic data on psychotherapy risks are lacking (Dimidjian & Hollon, 2010), it is widely believed that 
cognitive-behavioral and acceptance-based therapies pose a low level of risk to patients.  A recent large, 
well-conducted trial systematically measured adverse events associated with two psychotherapies for 
CBP similar to the psychotherapy under investigation here.  This trial reported that about one third of 
patients experienced a temporary increase in pain as a result of increased activity levels, and no other 
adverse events or serious adverse events were reported (Cherkin et al., 2016). In addition to temporary 
increases in pain, emotionally difficult material may arise during psychotherapy, which may cause 
psychological discomfort. 
 
Risks of blood sample collection:  The risks of blood draws via standard venipuncture technique are 
minimal and include pain, bruising at the venipuncture site, redness and swelling of the vein and 
infection, and a rare risk of vagovasal response. The dried blood spot kit involves a finger prick, which 
may cause mild discomfort. There is also a minor risk of bruising.  
 
Risks of EEG:   EEG is considered safe.  The electrodes only measure electrical activity, and do not 
administer any stimulations, so there is no risk of electrical shock.  Skin preparation for the electrode 
cap may cause minor discomfort. 
 
Ethical concerns:  There is no deception of either patients or treatment providers at any point during 
this study, and patients will not be prevented from seeking adjunctive treatment.  We believe there are 
no ethical concerns present regarding this treatment. 

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XVII. 
MANAGEMENT OF RISKS 
The risks associated with subcutaneous injection will be minimized by adhering to our injection 
procedure, (as detailed above; see the “Treatment (placebo study)” subsection within the “Research 
Design and Methods” section), adhering to standard safety protocols (i.e., Annersten et al., 2005; 
https://www.cc.nih.gov/ccc/patient_education/pepubs/subq.pdf, 2017), and by not administering the 
lower back subcutaneous injection within proximity to a significant cutaneous abnormality, including 
signs of infection (erythema, warmth, swelling, induration), an active wound, scar tissue, or other 
significant dermatologic abnormality. 
 
The MRI-related risks will be managed in the following way.  The MRI scan will be performed using an 
MR scanner employing pulse sequences and hardware that have been approved by the FDA for human 
clinical use. The field strength is 3 Tesla and all relevant operating characteristics (RF power deposition, 
rate of change of the field gradients, coil design) fall within the limits of FDA guidelines for NMR 
exposure. Participants will be carefully screened to exclude those who may have metal in or on their 
bodies that cannot be removed (e g., bullets, metal filings, body piercings, etc.). MR Facility rules strictly 
forbid staff from entering the magnet room carrying metal objects. Additionally,  
• 
Discomfort from scanner noise will be minimized with high-quality noise-blocking earbuds. 
• 
Discomfort from laying in the scanner will be minimized by making sure the subject is lying 
comfortably with head and neck supported. 
• 
With regard to PNS, participants are given a squeeze ball to use in case of an emergency. They 
are informed that if they experience PNS related sensations or are otherwise uncomfortable, 
they can alert the MRI technologist via the squeeze ball and the technologist will stop the scan 
immediately.  
• 
The risk of claustrophobia is minimized by screening subjects for self-reported claustrophobia.   
and, providing a mirror to see out, a button to signal distress, and an intercom.   
• 
Pregnant women are excluded to minimize risk to the fetus.  In accordance with standard INC 
procedures, female participants unsure as to whether they are pregnant will be given the 
opportunity to complete a urine pregnancy test immediately before the scanning period, and 
those with a positive result will not be scanned.  Alternatively, female participants may sign a 
waiver (attached) that they do not believe themselves to be pregnant. 
 
The risks associated with the pressure stimulations will be minimized in the following ways.  We will 
exclude participants who are hypersensitive to pressure pain or have difficulty to remove their fingers 
from the device when pressure is high using the calibration procedure. In addition, the pressure pain 
software has a “Stop” button, which can be used to stop the pressure stimuli anytime by experimenters. 
The participants will be given a hand-squeezable pneumatic signaling device for communicating with 
experimenters during scanning and therefore should be able to signal intolerable discomfort of any kind. 
The device is regularly maintained and tested by our trained personnel. All personnel who use the 
equipment are trained on equipment procedures. 
 
The risks associated with the back pain device will be minimized by performing an individual calibration 
for each participant testing how painful different levels of inflation are, as described above.  
Additionally, the device will be immediately deflated or removed from under participants’ backs upon 
request. The device is functionally equivalent to placing a pillow or rolled towel under a patients’ back—
it may be painful but cannot cause damage to the back, as ascertained in consultations with pain 
physicians. 
 

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The risks associated with psychotherapy will be minimized by emphasizing to participants that 
psychotherapy participation is optional, and they can always choose not to attend sessions while still 
completing all other aspects of the study.  Weekly supervision meetings among all therapists and the 
lead therapist, and a pain physician as needed, will also minimize risks by helping provide high quality of 
psychotherapeutic care to all patients in this study. 
 
Risks of blood sample collection will be managed through phlebotomy training of study personnel to 
ensure the use of proper standard technique to prevent complications and adverse events such as 
infection.  The risk of the blood spot will be managed by using an alcohol swab to clean the finger as well 
as a Band-Aid immediately after the blood collection.  
 
The risks associated with EEG will be managed by training all research personnel in EEG recording 
protocols. 
XVIII. POTENTIAL BENEFITS  
Subjects may experience a reduction in back pain from the treatment. 
 
The benefits to society stem from advancing scientific understanding of chronic pain, which 
imposes a large societal burden.  This study will a) be the first to test the efficacy of an 
open-label placebo injection for chronic back pain, and will provide an estimate of 
treatment efficacy, b) be the first open-label placebo study to include biological outcome 
measures, which are needed to establish the efficacy of this treatment, and c) provide a 
novel understanding of brain mechanisms supporting pain learning in a chronic pain 
population.  Additionally, this study will be the first to test the benefits of a psychotherapy 
with a novel psychoeducational component for CBP. 
XIX. 
PROVISIONS TO MONITOR THE DATA FOR THE SAFETY OF PARTICIPANTS 
A member of the research team will email or text subjects 3 days after receiving treatment to enquire 
about any adverse events.  We have found that email/text is the most reliable way to reach most 
subjects (subjects often do not answer their phone when called).  During the online pre-screening, we 
confirm with each subject that they are comfortable with email or text message communication, which 
is needed for completion of the daily surveys described above. 
 
Jonathan Ashar will monitor these reports and be responsible for reporting adverse events to the IRB. 
 
When half of the sample is collected, an interim analysis will be conducted on primary clinical outcome 
measures (i.e., PROMIS short forms).  If the effect of treatment vs. waitlist is small (i.e., d < .3), the study 
may be halted or revised (with IRB approval). 
XX. 
PROVISIONS TO PROTECT THE PRIVACY INTERESTS OF PARTICIPANTS  
CINC is a large facility that a person might enter for any number of reasons, and it does not clearly 
associate participants with any condition or state.  If participants are seen entering the Panorama 
Orthopedics and Spine Center, this will strongly suggest to an observer that they or a friend or family 

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member suffer from pain.  This is unavoidable.  Participants enroll in this study because they are seeking 
treatment for their pain, and for that reasons are presumably more than willing to enter a pain 
treatment clinic. All data collected will be coded with randomly assigned study IDs. 
XXI. 
MEDICAL CARE AND COMPENSATION FOR INJURY 
No research related injuries are expected.  In the event one does occur, no compensation is available. 
This is standard for all our research protocols and other protocols that we are familiar with, and is stated 
clearly in the consent form.  In case of any injury or discomfort we ask that participants contact us and 
will refer them to medical or psychological services as appropriate. For any complication resulting from 
the placebo treatment, we will refer them back to Dr. Karen Knight. 
XXII. 
COST TO PARTICIPANTS 
There will be no cost to participants.  Parking at CINC and at the Anschutz Medical Campus is free. 
XXIII. DRUG ADMINISTRATION 
Only placebo will be used.  The placebo will be 1mL of medical grade saline purchased from a supplier of 
medical equipment.  This will be “normal” saline (0.9% NaCl). 
 
XXIV. 
SHARING OF RESULTS WITH PARTICIPANTS 
There are no plans to share research results with participants.  Participants will be offered structural 
MRI images of their brain immediately after the second scan session. 
 
 

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