Project 1 Aim 2, Adaptations of the Brain in Chronic Pain With Opioid Exposure
Phase: PHASE2
Conditions: Opioid Use, Opioid Dependence, Opioid-use Disorder, Narcotic Use, Back Pain, Back Injuries, Chronic Pain, Chronic Low-back Pain, Pain, Chronic, Pain;Back Low;Chronic, Pain, Back
Sponsor: Northwestern University

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PROTOCOL TITLE: Project 1 Aim 2, Adaptations of the brain in chronic pain with opioid exposure
PRINCIPAL INVESTIGATOR:
A. Vania Apkarian, PhD Physiology 
Department 312-503-0404  
   a-apkarian@northwestern.edu
VERSION NUMBER: 8.0
VERSION DATE:  01Apr2023
STUDY SUMMARY:
Sample Size
80 Subjects
Funding Source
NIDA
Indicate the type of consent to be 
obtained
Written
Verbal/Waiver of Documentation of Informed 
Consent
Waiver of HIPAA Authorization 
Waiver/Alteration of Consent Process
 Lead Site ( For A Multiple Site Research 
Study)
Site
Data Coordinating Center (DCC)
Research Related Radiation 
Exposure
Yes 
No
Yes
DSMB / DMC / IDMC
No
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STATEMENT OF COMPLIANCE
The study will be conducted in accordance with the International Conference on Harmonisation 
guidelines for Good Clinical Practice (ICH E6), the Code of Federal Regulations on the Protection of 
Human Participants (45 CFR Part 46), and the NIH Terms of Award. All personnel involved in the 
conduct of this study have completed human subjects protection training.
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SIGNATURE PAGE
The signature below constitutes the approval of this protocol and the attachments, and provides the 
necessary assurances that this trial will be conducted according to all stipulations of the protocol, 
including all statements regarding confidentiality, and according to local legal and regulatory 
requirements and applicable US federal regulations and ICH guidelines.
Principal Investigator:
Signed:
Date:  
Name: A. Vania Apkarian
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TABLE OF CONTENTS
STATEMENT OF COMPLIANCE 
TABLE OF CONTENTS
LIST OF ABBREVIATIONS 
PROTOCOL SUMMARY
1
KEY ROLES AND CONTACT INFORMATION
2
OBJECTIVES
3
BACKGROUND
3.1 Innovation
3.2 Rationale
3.3 Preliminary Results Supporting Hypotheses
4
STUDY ENDPOINTS
5
STUDY INTERVENTION(S) / INVESTIGATIONAL AGENT(S):
6
PROCEDURES INVOLVED
6.1 Procedures for Aim1
6.2 Procedures for Aim 2
6.3 Details of Study Visit Procedures
6.4 Brain Imaging Procedures
6.5 Laboratory Procedures/Evaluations
6.6 Surveys and Questionnaires
7
DATA AND SPECIMEN BANKING
8
SHARING RESULTS WITH PARTICIPANTS
9
STUDY TIMELINE
10
INCLUSION AND EXCLUSION CRITERIA
11
RECRUITMENT METHODS
12
COMPENSATION FOR PARTICIPATION IN RESEARCH ACTIVITIES
13
WITHDRAWAL OF PARTICIPANTS
14
RISKS TO PARTICIPANTS
14.1 Risks from Procedures
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14.2 Risks from Medications
14.3 Emergency Care
14.4 Protections against Risk
15
POTENTIAL BENEFITS TO PARTICIPANTS
16
DATA MANAGEMENT AND CONFIDENTIALITY
16.1 Statistical Considerations and Power Analysis
16.2 Data Handling and Record Keeping
16.3 Data Management Responsibilities
16.4 Data Capture Methods
16.5 Types of Data
16.6 Confidentiality
17
PROVISIONS TO MONITOR THE DATA TO ENSURE THE SAFETY OF
PARTICIPANTS
17.1 Adverse Event Monitoring
17.2 Reporting of SAEs
17.3 Unblinding Procedures
17.4 Stopping Rules/Intervention Discontinuation
18
PROVISIONS TO PROTECT THE PRIVACY INTERESTS OF PARTICIPANTS
19
COMPENSATION FOR RESEARCH-RELATED INJURY
20
ECONOMIC BURDEN TO PARTICIPANTS
21
CONSENT PROCESS
22
PROTECTED HEALTH INFORAMTION (PHI AND HIPAA)
23
NON-ENGLISH SPEAKING PARTICIPANTS
24
QUALIFICATIONS TO CONDUCT RESEARCH AND RESOURCES AVAILABLE
25
REFERENCE LIST
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List of Abbreviations
ABC
The Addictions Behavior Checklist
ACS
Attentional Control Scale
AE
Adverse Event/Adverse Experience
ALT
Alanine Aminotransferase 
ANCOVA
Analysis of Covariance 
ASL
Arterial Spin Labeling
AST
Aspartate Transaminase
BP
Blood Pressure
BDI
Beck Depression Inventory
BUN
Blood Urea Nitrogen
CBC
Complete Blood Count
CBP
Chronic Back Pain
CBP + O
Chronic Back Pain with opioid use 
CBP - O
Chronic Back Pain without opioid use
CDC
Centers for Disease Control and Prevention 
CFR
Code Of Federal Regulations
COWS
Clinical Opiate Withdrawal Scale 
COMM
Current Opioid Misuse Measure
CPAQ
Chronic Pain Acceptance Questionnaire 
CRF
Case Report Form
DA
Dopamine
DHHS
Department Of Health And Human Services 
DMI
Drug Misuse Instrument
DMP
Prescription Monitoring Program
DTI
Diffusion Tensor Imaging
eACS
Emotional Attentional Control Scale
eCRF
Electronic Case Report Form
EDW
Enterprise Data Warehouse
ERQ
Emotional Regulation Questionnaire
FDA
Food And Drug Administration
FFMQ
Five Facets of Mindfullness Questionnaire 
fMRI
Functional Magnetic Resonance Imaging
GI
Gastrointestinal
GMV
Grey Matter Volume
g/dL
Gram Per Deciliter
H or HIPP
Hippocampus
HCP
Human Connectome Project
ICF
Informed Consent Form
ICH
International Conference On Harmonisation
IND
Investigational New Drug Application
IP
Investigational Product
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IRB
Institutional Review Board
ISM
Independent Safety Monitor
kg
killogram
LAQ
Loss Aversion Questionnaire
LOT-R
Life Orientation Test Revised
LSD
Least Significant Difference
MAIA
Multidimensional Assessment of Interoceptive Awareness
MEE
Morphine Estimate Equivalence
mg
Milligram
mL
Milliliter
MPQ
McGill Pain Questionnaire
mPFC
Medial Prefrontal Cortex
MRI
Magnetic Resonance Imaging
ms
millisecond
N
Number (Typically Refers To Participants)
NAc
Nucleus Accumbens 
NEOFFI
NEO Five Factor Inventory
NIDA
National Institute on Drug Abuse
NIH
National Institutes Of Health
NM
Northwestern Medicine
NMFF
Northwestern Medical Faculty Foundation
 NMH
Northwestern Memorial Hospital
NODDI
Neurite Orientation Dispersion and Density Imaging
 NRS
Numerical Rating Scale
NSAID
Non-Steroidal Anti-Inflammatory Drug
 NU
Northwestern University
NUCATS
Northwestern University Clinical and Translational Sciences Institute
OA
Offset analgesia
ODI
Oswestry Disability Index
OUD
Opioid Use Disorder
PANAS
Positive And Negative Affect Schedule
 PASS
Pain Anxiety Symptoms Scale
PCS
Pain Catastrophizing Scale
PDQ
painDETECT Questionnaire
PET
Positron Emission Tomography
PFc
Prefrontal Cortex
pg
Picogram
PHI
Protected Health Information
PI
Principal Investigator
PRO
Patient Reported Outcome
PSQ
Pain Sensitivity Questionnaire
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rsfMRI
Resting State Functional Magnetic Resonance Imaging
SAE
Serious Adverse Event/Serious Adverse Experience
SBP
Subacute Back Pain
SBPp
Subacute Back Pain-Persisting Phenotype 
SBPr
Subacute Back Pain- Recovering Phenotype
 SGOT
Serum Glutamic Oxaloacetic Transaminase 
SGPT
Serum Glutamic Pyruvic Transaminase
SNI
Spared-Nerve-Injury
SNRI
Serotonin-Norepinephrine Reuptake Inhibitor
 SOP
Standard Operating Procedure
SOWS
Subjective Opiate Withdrawal Scale 
SSRI
Selective Serotonin Reuptake Inhibitor
Unit/L
Unit Per Liter
UDT
Urine Drug Test
US
United States
VTA
Ventral Tegmental Area
WOCBP
Women Of Childbearing Potential
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PROTOCOL SUMMARY
Title:
Project 1, Adaptations of the brain in chronic pain with opioid exposure
Summary:
In this project, we will study brain reorganization and behavioral responses in 
chronic pain with opioid exposure in CBP
Objectives:
Aim 1 of this study is being carried out under IRB approved STU00207384.
Aim 2a: In a double-blind, randomized, placebo-controlled crossover clinical trial, 
we track brain functional changes in individuals with i) CBP+O, and individuals 
with ii) CBP+OUD following a brief drug delay and re-exposure manipulation; re- 
exposure could be placebo, the participant’s own opioid dose, or a dopaminergic 
treatment (50% of groups I & ii in Aim 1a, n=40/group).
Aim 2b: Track changes in motor, cognitive and emotional abilities and related 
brain properties, with brief opioid delay and re-exposure (all participants of aim 
2a)
Aim 2c: To assess the dopamine dependence of OA induced by thermal 
stimuli in participants with chronic pain
Population: Sample size: 80
Gender: Male and Female 
Age: 18 years and older
Demographic group: No racial/ethnic restrictions
General health state: generally good health
Phase: 2
Number of Sites: 2
Northwestern University, Chicago, IL 60611 
Shirley Ryan Ability Lab. Chicago, IL 60611
Study Duration: 50 months
Participant Participation Duration: Up to 8 weeks
Estimated Time to Complete Enrollment: 48 months
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1.
KEY ROLES AND CONTACT INFORMATION
Principal Investigator: 
Apkar Vania Apkarian, PhD Professor
Department of Physiology
300 E. Superior Street, Room7-705
Chicago, Illinois 60611 
Phone: (312) 503-0404
Fax: (312) 503-5101
Email: a-apkarian@northwestern.edu
Medical Monitor:
TBD
NIH Program Official: TBD
Co-Investigators:
Thomas J. Schnitzer, MD, PhD, Professor 
Department of Physical Medicine & Rehabilitation
710 N. Lake Shore Drive, Suite 1020 Chicago, IL 60611 
Phone: (312) 503-2315 
Fax: (312) 503-1505
Email: tjs@northwestern.edu
James W. Griffith, PhD 
Northwestern University 
633 N. St. Clair, 19th floor
Phone: (312) 503-5345
Fax: (312) 503-4800
Email: j-griffith@northwestern.edu
Clinical Site Investigator: 
Thomas J. Schnitzer, MD, PhD, Professor
Department of Physical Medicine and Rehabilitation
710 N. Lake Shore Drive, Room 1020
Institutions:
Northwestern University Chicago, IL 60611
Other Key Personnel:
Data Analyst:
James W. Griffith, PhD 
Northwestern University 
633 N. St. Clair, 19th floor 
Phone: (312) 503-5345
Fax: (312) 503-4800
Email: j-griffith@northwestern.edu
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2.
OBJECTIVES:
Aim 1 is included in an already approved study under STU00207384.
Specific Aim 2:
Primary Outcomes 
2.a. DA+NSAIDs and opioids provide superior pain relief compared to placebo in patients with CBP.
The effect of the treatment on pain will be measured using a numeric rating scale (NRS) before and 
after treatment.
Hypothesis: Distinct changes will be seen in pain relief in subgroups treated with 
Carbidopa/Levodopa +Naproxen, opioid, and placebo. 
Secondary Outcomes
2.b. DA+NSAIDs are non-inferior in pain relief compared to opioids in patients with CBP.  
      The effect of the treatment on pain will be measured using a numeric rating scale (NRS) before 
and after treatment.
Hypothesis: Distinct changes will be seen in pain relief in subgroups treated with DA+NSAIDs, opioid, 
and placebo. 
2.c. DA+NSAIDs and opioids provide superior withdrawal relief compared to placebo.
The effect of the treatment on withdrawal will be measured using the Pain and Craving Index (PCI) 
and Subjective Opiate Withdrawal Scale (SOWS) before and after treatment
Hypothesis: Distinct changes will be seen in withdrawal relief in subgroups treated with DA+NSAIDs, 
opioid and placebo.
2.d. DA+NSAIDs are non-inferior in withdrawal relief compared to opioids in patients with CBP.
      The effect of the treatment on withdrawal will be measured using the Pain and Craving Index 
(PCI) and Subjective Opiate Withdrawal Scale (SOWS) before and after treatment
Hypothesis: Distinct changes will be seen in withdrawal relief in subgroups treated with DA+NSAIDs, 
opioid and placebo. 
2.e. Use a moderated mediation analysis to investigate how brain properties (functional and 
structural connectivity, brain morphology) affects pain and withdrawal before and after treatments.
      We will probe whether different neurocircuitry – descending pain modulation (i.e., periaqueductal 
grey) and the cortico-mesolimbic system (i.e., nucleus accumbens, medial prefrontal cortex, 
hippocampus, insula, anterior cingulate, somatosensory cortex) – are impacted differently by each 
treatment modality, further elucidating the neuromechanisms of pain analgesia and opioid 
withdrawal. 
Hypotheses:
1) Human brain activity and functional network properties perturbed with psychological opioid 
withdrawal can be parceled to specific responses, identified with re-exposure to placebo, opioid, and 
DA+NSAID.
2) The relationship of re-exposure responses to analgesia/hyperalgesia and to OUD will identify 
respective brain areas and networks, revealing separation/overlap between pain and OUD reward-
related circuits.
3) DA+NSAID may be a viable alternative for opioid use in a subgroup of CBP exploratory 
outcomes: 
Exploratory outcomes
2.f. Evaluate the same outcomes between subjects with different chronic pain conditions.
2.g. Compare treatment effects on withdrawal symptoms between opiate dependent subjects with 
and without chronic pain. 
 
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3.
BACKGROUND:
The overall premise of this project, and of our Center, is that opioid analgesia and opioid addiction have 
important interactions with the brain pathways involved in chronic pain, and that these interactions, in 
time, exacerbate opioid use disorder and diminish opioid analgesic efficacy. Opioids are the most 
efficient analgesics and the only source of immediate relief from severe pain, including post-operative 
pain and palliative care (mainly for cancer patients). However, opioid abuse is a major health care 
problem. The most recent CDC report 2 states that, from 1999 to 2014, more than 165,000 people died 
in the US from overdoses of prescription opioids. At least half of all US opioid overdose deaths involve 
a prescription opioid 3, and as many as 1 in 4 people who receive long-term prescription opioids for non- 
cancer pain struggle with addiction. Indeed, in 2014 alone, more 
than 14,000 people died from overdoses of prescription 
opioids. Because chronic pain is commonly treated with opioids 
and 116 million people in the US have chronic pain, opioid 
abuse is intimately linked with the management of chronic pain.
The brain circuitry that is functionally reorganized in chronic pain overlaps extensively with the circuitry 
involved in affective evaluation, motivation and drug addiction -- including opioid addiction4-15(fig. 1). What 
we don’t know is how opioids affect the brain reorganization resulting from chronic pain, or how this 
reorganization affects the abuse potential of opioids and the resulting clinical response. There are several 
line of evidence suggesting that there is an interaction. First, in contrast to acute pain, the evidence that 
opioids potently reduce chronic non-cancer pain is not convincing 16-18. In fact, recent studies suggest that 
opioids are not superior to non-steroidal anti0inflammatories in managing chronic pain19-23. Nevertheless, 
opioids continue to be used to manage chronic pain, since there seems to be some consensus amongst 
clinicians that the long-term management of pain with opioids can be beneficial, or at least safe with 
appropriate patient selection and dose titration24-26, despite current CDC recommendations contradicting this 
view 27. But the basic science regarding the interaction between mechanisms of chronic pain and of long-
term opioid use remains essentially unexplored. In a testimonial to Congress, the director of NIDA states: 
“Little is yet known about the risk for addiction among those being treated for chronic pain or about how 
basic pain mechanisms interact with prescription opioids to influence addiction potential.”
Chronic pain itself affects humans at epidemic proportions – more than the total affected by heart 
disease, cancer, and diabetes combined. Chronic pain also costs the US over half a trillion dollars each 
year in medical treatment and lost productivity 28. A World Health Organization report indicates that 
chronic pain is the top source of disability in the US, and the 6th largest disability source worldwide 29. 
Epidemiological studies show that 1 in 5 individuals suffers from chronic pain30-36. Most often, chronic 
pain persists for a lifetime. Despite a considerable research effort, there is no generally effective therapy 
for chronic pain.
The extent of association of opioid treatment in CBP with drug abuse/addiction is unclear. 
Inconsistencies in addiction terminology hamper efforts to define and quantify opioid abuse arising as a 
direct result of opioid pain treatment (iatrogenic opioid addiction). Repeated administration of any opioid 
almost inevitably results in tolerance and physical dependence 37,38. In contrast, addiction occurs only 
in a small percentage of patients exposed to opioids 37. Only a few studies have examined the prevalence 
of OUD (signs and symptoms associated with drug abuse which may reflect addiction) among patients 
receiving opioids. In patients with CBP receiving opioid treatment, the prevalence of substance use 
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disorders ranges from 3% to 43%, with a lifetime prevalence as high as 54% 39-41, and the true prevalence 
most likely remains unknown.
The traditional view regarding mechanisms of chronic pain has emphasized the role of injury-induced 
enhanced nociceptive signaling (end organ-driven peripheral sensitization) and related spinal cord 
synaptic changes giving rise to spinal sensitization 42-45. But it is clear that the brain has a major impact 
on chronic pain. Many lines of clinical observation demonstrate that the characteristics of the peripheral 
injury are not sufficient to explain the chronicity of the pain response. With the advent of human brain 
imaging technology, it became possible to peer inside the brain of patients. A series of studies, pioneered 
by the Apkarian lab, provided clear evidence that chronic pain is associated with abnormal brain anatomy 
and physiology 46-51. These observations have now been replicated for many chronic pain conditions 52,53, 
and establish that the circuitry involved in chronic pain cannot be deduced from that responsible for acute 
pain. Since all prior brain imaging studies of chronic pain had been cross-sectional in nature, they were 
not able to distinguish between causes and consequences. To directly address this issue, we performed 
the first prospective observational brain imaging based study, following back pain patients for up to three 
years after an initial acute/sub-acute back pain episode. In subjects whose back pain persisted (i.e., who 
transitioned to chronic pain), a time-dependent re-organization of the brain anatomy and functional 
connectivity was observed 54. The emergence of chronic pain was not dependent upon the initial intensity 
of back pain, or related brain activity. Rather, persistent and recovering pain groupings could be predicted 
within weeks of onset of back pain, based on anatomical and functional biomarkers of the brain circuitry. 
Various properties of this circuitry accurately (>80%) predicted subjects who would develop chronic pain. 
These included: 1) functional connectivity between mPFC and NAc 54, 2) white matter myelination and 
branching differences in fiber tracks underlying the mesolimbic system 55, 3) intrinsic and cortical 
connectivity of the hippocampus (H) 56, 4) volumes of H and amygdala (Amy) 57 (fig. 2), and 5) white 
matter and functional connectivity of the limbic circuitry linking the mPFC, NAc and Amy 57. Altogether
these observations showed that properties of the limbic brain determine individuals’ risk for chronic pain. 
Many of these same biomarkers are commonly associated with addiction 54-59.
In summary, there is a huge disconnect between the magnitude of the opioid epidemic and the degree of 
scientific knowledge regarding the underlying mechanisms involving appropriate and inappropriate opioid 
use. The CBP patient population, the largest group of chronic pain patients worldwide, is perhaps the type 
of chronic pain most exposed to opioid use and its untoward consequences. Since our scientific 
knowledge of the underlying mechanisms of chronic pain is best known in CBP and in the rodent SNI 
pain model, we have a unique opportunity to study opioid exposure in these complementary conditions.
The central hypothesis to be tested, is that continued exposure to opioids exacerbates brain 
maladaptive plasticity that defines chronic pain, diminishing analgesic efficacy, and increasing the risk of 
opioid abuse. Therefore, we will examine brain reorganization relative to chronic pain with opioid 
exposure, in various CBP subgroups (CBP in patients properly managed with opioids [CBP+O], CBP in 
patients with mild/moderate opioid use disorder [CBP+OUD], CBP managed without opioids [CBP-O] and 
healthy controls (Aim 1); when such patients (CBP+O, CBP+OUD) undergo a brief drug delay and re- 
exposure with placebo, opioids, or DA+NSAID (Aim 2); In all subjects in Aims 1 & 2 we will also track 
cognitive, emotional, and motor abilities, and their perturbations with drug delay and re-exposure, and 
relate them to brain adaptations.
3.1Innovation
1. Overall: This project is the first systematic investigation of the mechanisms regarding the interaction 
between chronic pain and opioid exposure in humans. This gap in knowledge was pointed out back in 
2009 by the American Pain Society Guideline on the topic 25.
2. Conceptually, our study is designed to challenge the traditional view, which distinguishes between 
mechanisms of opioid analgesia and opioid addiction in chronic pain. While we are the first to formulate 
this concept, it is based on solid scientific evidence.
3. Hypotheses proposed are all novel, and should be considered somewhat speculative. Thus, we also 
expect surprises.
4. From an experimental design viewpoint, our studies are novel because we study the impact of opioid 
exposure on the brain cross-sectionally, and evaluate within-subject brain properties when drug exposure 
is manipulated.
5. We have pioneered the concept of using multimodal brain imaging in pain research, an approach that 
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has led to uncovering the fundamental mechanisms that provide the background for this project. We 
extend these studies in this protocol utilizing state-of-the-art analysis methods, combined with assessing 
pain, opioid exposure and abilities, to provide a comprehensive study of properties of the condition, and 
integrate mechanisms across physiological domains.
6. We continue to develop novel measurement tools to study the brain in pain, including:
a)
Graph theoretical methods and global network measurements to assess brain properties (figures 
5-7).
b)
Off-site large datasets used as unbiased ground-truth controls, compared to our own data (T1, 
DTI, rsfMRI: C1000 (Connectome1000), n = 1000 subjects, HCP (Human Connectome Project) 
data n = 900 subjects) (figures 5, 6).
c)
Use of multi-shell diffusion imaging to differentiate the microstructure of grey matter 70,71.
d)
Here we begin using state-of-the-art 3D pseudo-continuous arterial spin labelling (ASL), an MRI- 
based technique to measure cerebral perfusion, which provides the means to calculate absolute 
rates of human brain metabolism 72.
e)
We also have adapted a new data analysis blinding method to diminish data processing biases 
and enhance reproducibility (see 73). Moreover, to ensure that obtained results are rigorous and 
generalizable, data are collected in two separate labs, on two separate, but identical brain 
scanners (NU & AbilityLab), and are used for discovery and validation. Although the data are 
collected independently, all brain imaging data analyses are done (blinded) using the same tools 
and software.
3.2 Rationale
The traditional view is that independent brain circuits mediate opioid analgesia and opioid 
reward/addiction 37. Specifically, it is assumed that opioid analgesia is mediated through descending 
modulation of the spinal cord by PAG opioidergic neurons and by opioid interneurons in the spinal cord 
that regulate nociceptive signalling. In contrast, opioid reward/addiction is thought to be mediated by 
the mesolimbic system, which controls hedonic, affective and motivational aspects of behaviour 16,37,74, 
see fig. 1. Our work shows that this presumed separation between analgesia and opioid addiction is 
not tenable in chronic pain. Besides our human studies, the results from the cellular examination of NAc 
physiology shows strong correspondences between opioid addiction and the transition to chronic pain. 
Chemogenetic modulation of dopamine D2 spiny neurons in the medial shell of NAc (d2SPNs in NAc 
shell) effectively and bi-directionally controlled tactile allodynia in SNI mice, showing that this NAc network 
causally influences analgesia. Complementing these results, it has recently been shown that morphine 
decreases d2SPN excitability 75. Additionally, VTA DA neurons exhibit increased tonic inhibition with 
chronic administration of morphine thus reducing DA inputs to NAc 76. Similarly, in SNI, the ongoing firing 
rate of VTA DA neurons are decreased and DA concentration within NAc is concomitantly decreased 
65. These results support our central hypothesis that chronic pain primes the limbic brain for opioid 
addiction. However, virtually nothing is known about how opioids, particularly repeatedly self- 
administered opioids, affect the re-organization of brain circuits in the chronic pain state, nor how this state 
changes the actions of opioids in humans.
Neuroimaging of opioid dependence and addiction has been studied mainly for illicit opioids. Most human 
neuroimaging research has focused on the acute effects of opioids on experimentally-induced pain in 
healthy subjects 18,77-80. Observations from such studies show that activations in mesolimbic regions are 
maximally suppressed at the lowest opioid dose, consistent with the high opioid receptor densities seen 
throughout the limbic brain (fig. 1). Clinical research on the neurobiological aspects of opioid dependence 
on brain systems has focused on illicit opioids 81-84. Two human neuroimaging studies are relevant to our 
project. A cross-sectional study in 10 opioid dependent individuals (without pain, relative to 10 age- 
matched controls) showed bilateral volumetric loss in Amy, and decreases in functional connectivity in the 
anterior insula, NAc and Amy 85. In a longitudinal MR study 86, 10 CBP patients were administered oral 
morphine daily for 1 month, and compared to those who used placebo. Significant volumetric differences 
were observed in Amy and this effect was persistent 5 months after cessation of treatment. Results from 
both studies are consistent with our main tenet that opioid exposure impacts mesolimbic anatomy and 
function, exaggerating maladaptive changes of chronic pain.
Overall, the science of the interaction between chronic pain and opioid exposure is minimally explored. 
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The current project is therefore designed to unravel the relationship between opioid analgesia and abuse 
potential from a mechanistic viewpoint.
Mechanisms to explain known risk factors for OUD remain unknown. We propose to define brain 
biomarkers to provide mechanistic support for OUD risk factors. Women comprise a majority of all chronic 
pain populations 87, receive more prescriptions for – and exhibit use of – higher doses of opioid analgesics
88. Reports of higher rates of opioid misuse in women may result from: a) greater chronic pain prevalence,
b) distinct hormone-dependent mechanisms mediating opioid analgesia and tolerance to chronic 
morphine 87,89, and c) higher rates of anxiety and depression, which positively correlate with opioid misuse
88. Sex differences in opioid-induced analgesia in chronic pain remain controversial, given that most 
human and rodent studies are conducted in healthy individuals exposed to acute pain 90. Therefore, we 
expect important differences both in behavioral outcomes and brain properties of female CBP, with opioid 
exposure. We will test the sex dependence of all of our primary outcomes.
Chronic pain patients with opioid use disorder exhibit high rates of psychiatric comorbidities, including 
anxiety and mood disorders 91. CBP itself is commonly associated with various comorbidities 92. In the 
past, we studied CBP at the exclusion of comorbidities; but here, we will include CBP patients with 
comorbidities. We expect that these will exacerbate opioid abuse liability, particularly since mood and 
pain comorbidities also impact on the limbic system. Moreover, we attempt to make the present study 
concordant with the common clinical population. Therefore, we will test the influence of comorbidities on
brain adaptations.
The majority of people exposed to drugs of addiction are resilient, and only a minority are vulnerable 
to addiction 93. The same is true for opioid use disorder 37,94, and for developing chronic pain. Therefore, 
we assume that subsets of our CBP patients will show signs of vulnerability. Therefore, identifying brain 
biomarkers associated with OUD resilience is a primary objective in humans (Aim 1).
Aim 2 attempts to untangle pain and opioid dependence circuits. There are no studies that we know of, 
regarding brain imaging of brief opioid withdrawal and re-exposure in chronic pain. The general addiction 
literature amply demonstrates that originally neutral stimuli regularly associated with drug intake become 
conditioned stimuli and evoke drug craving by stimulating an appetitive response 95. Conditioned drug cues 
also activate counter adaptive homeostatic mechanisms that induce conditioned withdrawal if 
subsequent drug consumption does not occur; drugs are then craved to abolish withdrawal symptoms 
and negative mood states. Stimulation of an appetitive response involves activation of the DAergic reward 
system and its opioidergic inputs 
96, while activation of conditioned withdrawal includes a 
glutamatergic/GABAergic imbalance with increased excitatory and decreased inhibitory transmission 97. 
How these circuits become distorted with chronic pain managed with repeated opioid exposure, 
occasionally leading to the OUD state, is the question we address by mildly perturbing the system with a 
transient, open-labeled withdrawal followed by a blinded re-exposure in Aim 2. Given that pain relief is 
intrinsically rewarding, chronic pain places the organism in a complex state where the euphoric and pain- 
relieving rewarding values of opioids are presented together repeatedly, within a state that is primed for 
addiction due to limbic maladaptations  as a result of the chronic pain itself. Thus, these interactions are 
complex, and they are time- and dose- dependent as well.
In Aim 2, we re-expose participants (CBP+O and CBP+OUD) to DA+NSAID in order to assess 
behavioral responses and test brain responses. We expect that in some subjects, DA+NSAID will 
replicate brain opioid effects. This will provide evidence for the utility of replacing opioids with this non- 
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addictive therapy for chronic pain. Our approach follows from data we have generated and the fact that 
transmission within DAergic mesolimbic circuitry is consistently affected by all drugs of abuse. Further, 
human brain imaging studies of drug dependence provide similar consistent evidence 98 We have done 
so, initiating a clinical trial to test whether this treatment (twice a day for 3 months) would diminish 
transition to chronic pain in subjects with early back pain. The study remains blinded. More than 50 
participants have completed the study. We observe minimal adverse side effects and no signs of 
addiction. Administering DA+NSAID in CBP is thus safe. Importantly, it should mimic opioid control of 
CBP, as the NSAID should provide an analgesic effect while DA will be activating DAergic circuits that 
opioids would also induce. This combination treatment is thus potentially a non-addictive alternative to 
managing chronic pain with opioids.
Offset analgesia (OA) is a pain psychophysical phenomenon best described as “disproportionately 
large decreases in pain ratings evoked by small decreases in [nociceptive] stimulus intensity”127. 
While many healthy individuals experience a complete analgesic response, OA is blunted in those 
with chronic pain. On average, chronic pain patients have a 30% lower OA response than healthy 
controls, and it is the only known psychophysical pain assessment that is markedly impaired in pain 
patients128. There is reason to believe such findings are mediated by the limbic circuitry—the same 
circuity that are involved in addiction129. Data from our group demonstrate that, upon removal of a 
nociceptive stimulus, nucleus accumbens is activated in healthy controls (reward of pain relief), but 
deactivated in chronic pain patients (punishment)130. Moreover, brain activity in the limbic circuitry is 
distinct between healthy individuals and patients with chronic pain131. These findings are reflected by 
a body of work suggesting chronic pain is maintained by altered limbic pathways132. If limbic pathways 
are responsible for OA, then OA may noninvasively probe the circuity at the epicenter of chronic pain 
and drug abuse. By pharmacologically perturbating dopamine levels, we can assess the dopamine 
dependence of OA. Therefore, we will incorporate a brief OA protocol into our existing study to 
assess the dopamine- dependence of OA in chronic patients on opiates. If OA is dopamine 
dependent, we expect L-dopa to amplify OA, while placebo and opiates will not have any effect. Such 
a finding will advance our knowledge of OA and the limbic circuity in general, pointing to a new 
mechanism of analgesia and a way to noninvasively prone the pain and addiction circuitry.
3.3 Preliminary results supporting proposed hypotheses.
1)
Long-term opioid exposure in CBP is associated with smaller 
limbic volumes. We compared Hipp volumes in matched 
CBP groups, one managed exclusively with opioids and one 
not, and healthy matched controls. The volumes of right and 
left Hipp were calculated for each subject. Group 
comparisons were performed using an ANCOVA with 
volume as the dependent factor, the group as categorical 
factor, and age and gender as covariates of no interest. 
Since the number of subjects was small, pairwise post-hoc 
comparisons were performed using a Fisher- LSD test. We 
observed significant group differences (right Hipp: F2, 13 = 
18.1, p = 0.0001, and left Hipp: F2, 13 = 17.2, p = 0.0002). As 
in our previous report 57, both CBP groups exhibited smaller 
Hipp volumes compared to health subjects. More 
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importantly, we observed that CBP patients on opioids 
showed an additional reduction
in Hipp volumes compared to CBP not on opioids (fig. 4). These results suggest opioid use in CBP 
impacts limbic structures, reinforcing our primary hypothesis.
2) The brain connectome in chronic pain. We recently addressed the reverse question: is there a brain 
signature for the state of chronic pain that can be generalized across types of chronic pain? We used 
rsfMRI employing graph theoretical techniques to calculate nodal degree maps in individual subjects
100.
The approach tests the general concept that chronic pain may 
be characterized as an abnormal brain network state. Brain 
graphs were derived from 5,828 regional cortical and 
subcortical nodes, with edges (16,979,878 total possible) 
drawn between nodes to represent their functional 
correlation
in CBP patients (n=25) and age- and gender-matched healthy 
controls (n = 75) 100. We used a unitary measure which 
assesses whole-brain degree rank order disruption (kD), 
defined as the gradient fitted to the mean difference
in nodal degree between any given subject in relation to the 
mean nodal degree in a control population. CBP, but not our 
healthy group, showed significant degree rank order
disruption (unpaired t-test = - 14.84, p < 0.00001); and individual kD scores strongly correlated with intensity 
of back pain. We observed a similar relationship for other
chronic pain conditions and in rodent models of chronic 
pain (SNI).
3) Distortion of brain connectome in a CBP with a 24-hr
opioid withdrawal. We examined global and local functional reorganization associated with opioid 
withdrawal (24 hours) in one patient who was on opioid therapy for years. Opioid withdrawal was 
associated with an increase in the magnitude of spontaneous pain from 7 out of 10 to 9 out of 10. We 
observed rank order disruption similar to that observed in CBP patients (Fig. 5). To investigate local 
nodal degree changes following opioid withdrawal, we identified the top 1% of voxels showing either 
increased or decreased functional connectivity between the 2 scans (Fig. 6A).
Opioid withdrawal increased nodal degree in bilateral primary and secondary sensory regions and ACC, 
and decreased nodal degree in frontal regions and Amy (Fig. 6B). We acknowledge that these results are 
not placebo controlled, and may also be due to changes in pain.
Given the results 2) and 3) we will use kD scores in all rsfMRI data (human and rat) to assess the 
global impact of opioid exposure on the brain in chronic pain.
4)
Long-term opioid exposure distorts VTA functional connectivity. This relationship was evaluated in 21 chronic 
pain subjects managed with opioids vs. 21 matched chronic pain managed without opioids. These results are 
not corrected for physiological confounds (not available) and thus are only suggestive (fig. 7).
5)
Brief opioid withdrawal and re=exposure distorts brain metabolism and VTA connectivity. In two CBP+O 
participants, we implemented parts of the paradigm for aim 2. Fig. 8 shows ASL and rsfMRI changes in one 
subject.
6)
Opiate preference and opiate analgesia show injury type and time dependence (fig. 2 in Overall). Our 
preliminary MCPP experiments in SNI/sham mice, 5 days and 30 days after injury (n=8/group), showed 
morphine place preference acquisition and post MCPP tactile allodynia were dependent on the groups by time 
interaction, with acquisition being stronger in SNI at 30 days, and allodynia stronger at 5 days.
7)
Brain metabolism differences between SNI and sham rats, with a single dose of morphine (fig. 9). Our 
preliminary PET FDG results show overall decrease in brain metabolism in SNI & sham rats 1-hour after 
5mg/kg morphine, as well as localized between group differences.
4.
STUDY ENDPOINTS
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Specific outcomes for Aim 2a: We have piloted this protocol in 2 CBP+O patients, and adjusted 
the paradigm accordingly. Preliminary results are very encouraging as we observed robust changes in 
metabolic activity and in VTA functional connectivity between opioid delay and re-exposure (fig. 8). An 
issue we have encountered is that opioid re-exposure may induce somnolence. Thus, scans might require 
a minimal task to test for wakefulness, for example, implementing a visual fixation point which slowly 
changes in color during scanning. Participants will then be instructed that at the end of each scan, we will 
interrogate them as to the properties of the point. We have also tested the monitoring of heart rate and 
breathing, which will be collected regularly and used as confound covariates. Given rodent evidence that 
DA involvement in opiate reward is enhanced with dependence 113, brain responses to DA+NSAID should 
be related to OUD. This design requires subjects spending 3 full days with us, but has not been a problem 
in the 2 participants studied thus far, although other candidate subjects were wary about the extent of time 
needed. Given the limited number to be enrolled (80 over 5 years), we are confident this trial goal is readily 
achievable.
Specific outcomes for Aim 2b: Our pilot results show specific changes in abilities, depending on the type 
of re-exposure. Brain activity and connectivity changes that would reflect shifts in ability remain to be 
identified. These results complement the data collected in aim 1b, and together they have the potential 
to clarify the specific influence of both chronic pain and opioid exposure on human abilities.
5. STUDY INTERVENTION(S)/ INVESTIGATIONAL AGENT(S):
5.1 Carbidopa/levodopa, SINEMET®
1) Name: Carbidopa/levodopa, SINEMET®
2) Composition: Carbidopa/levodopa is a white, crystalline compound, slightly soluble in water.
3) Storage and Handling: Carbidopa/levodopa will be maintained in a controlled environment between
15⁰C-300⁰C. It will be stored in a secure location by the
NMH investigational pharmacy. . Carbidopa/levodopa has a 6-month shelf-life.
4) Dose: 25mg carbidopa/ 100mg levodopa
5) Administration: Carbidopa/ levodopa will be administered once per patient. Carbidopa/levodopa will 
be administered alongside naproxen.
6) Masking: The Carbidopa/Levodopa tablets supplied by the manufacturer will be overencapsulated 
at Northwestern Memorial Hospital Pharmacy by putting the supplied tablet inside of another capsule and 
filling the remaining space with excipient. The excipient for the capsules will be Lactose NF. A 00 hard, 
gelatin, opaque capsule will be used.
7) Acquisition: Carbidopa/levodopa will be sourced via Northwestern Memorial Hospital (NMH) Pharmacy.
5.2 Naproxen
1) Name: Naproxen
2) Composition: Naproxen is an odorless, white to off-white crystalline substance, practically insoluble 
in water at high pH.
3) Storage and Handling: Naproxen will be maintained in a controlled environment between 15⁰C-30⁰C. 
It will be stored in a secure location by the NMH investigational pharmacy. The expiration date of the 
naproxen will vary based on when it is acquired and will be documented and monitored closely.
4) Dose: 500mg
5) Administration: Naproxen will be administered once per patient. Naproxen will be 
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administered alongside carbidopa/levodopa.
6) Masking: The naproxen supplied by the manufacturer will be overencapsulated at NMH Pharmacy 
by putting the supplied tablet inside of another capsule and filling the remaining space with excipient. The 
excipient for the capsules will be Lactose NF. A 00 hard, gelatin, opaque capsule will be used. This will differ 
in color from the capsule used for the carbidopa/levodopa.
7) Acquisition: Naproxen will be sourced via NMH Pharmacy.
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5.3 Placebo
A matching capsule containing lactose will be prepared by NMH pharmacy. The appearance and 
properties of these capsules will be identical to those containing the active treatment and all labeling will be 
identical other than participant identifier. Placebo capsules of both colors will be prepared as all participants will 
receive 2 capsules at each treatment episode.
5.4 Opioid
All participants will be on a short-acting opioid medication. They will be instructed to not take their regular 
morning opioid dose. Using the online Prescription Monitoring Program (PMP), the clinical investigator will 
confirm participant’s opioid medication and order a single dose of the medication from NMH investigational 
pharmacy. The pharmacy will fill and over encapsulate the prescribed medication in a 00 hard, gelatin, opaque 
capsule which will be identical to the other non-naproxen treatment options.
Protocol will be updated on changes based on drug availability and investigational pharmacy, as appropriate.
5.5 Masking
After confirming the participant’s opioid medication using the PMP, the clinical investigator will order a 
single dose of the participant’s medication from NMH investigational pharmacy. The pharmacy will fill and 
over encapsulate the prescription accordingly. The pharmacy will have the allocation tables for the study. 
Each new participant will receive the next study ID number and receive the appropriate sequence of drug from 
the pharmacy. Participants will receive a different treatment option for their initial treatment period at each of 
the 3 imaging visits.
Each treatment period will consist of three capsules: a red, blue and purple capsule. The red 
capsule will always either be l-dopa/c-dopa or placebo for l-dopa/c-dopa. The blue capsule will always 
either be naproxen or placebo for naproxen. The purple capsule will always either be active opioid or 
placebo for opioid.
In the event that a participant is taking multiple opioids, an additional placebo pill will be prepared 
per additional opioid dose taken to maintain the blind.
Depending on the allocation table, "treatment period 1" will be one of the following three sequences:(1) l- 
dopa/c-dopa, naproxen, and placebo for opioid (2) placebo for l-dopa/c-dopa, placebo for naproxen and active 
opioid or (3) placebo for l-dopa/c-dopa, placebo for naproxen, and placebo for opioid; "treatment period 2" will be 
one of the following three sequences: (1) placebo l-dopa/c-dopa, placebo for naproxen, and active opioid (2) 
placebo for l-dopa/c-dopa, placebo for naproxen, and placebo for opioid or (3) placebo for l-dopa/c-dopa, placebo 
for naproxen and active opioid; respective to "treatment period 1." This is demonstrated below:
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The pharmacy will have two containers, one labeled “treatment period #1” and the other labeled 
“treatment period #2.” They will place the determined appropriate treatment in each container, 
respectively, and give the containers back to the blinded staff who will administer the treatments 
accordingly.
Individuals who are allergic or cannot tolerate naproxen or l-dopa may still be enrolled but will have only 
2 imaging visits, receiving either opioid or placebo at each visit based on their treatment allocation.  All 
other procedures will be identical.
6. PROCEDURES INVOLVED:
Potential eligible subjects will be identified from existing clinical practices at NU and AbilityLab, and will 
be contacted by phone, and if eligible and willing, invited to participate.
6.2 Procedures for Aim 2:
6.1 Procedures for Aim 1
Procedures for Aim 1 are carried out under IRB approved STU00207384.
6.2 Procedures for Aim 2
For new participants and those who participated in Aim 1 more than three months prior to starting Aim 
2, there will be an additional screening visit. These participants will have four visits in total (Screening, 
Visit 1, Visit 2, and Visit 3). At the screening visit, participants will first be consented and if they meet 
inclusion/exclusion criteria will continue on to the remaining procedures of the visit. The screening 
visit will also require participants to complete questionnaires (in REDCap) regarding their general 
health, pain, function, mood and personality.
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For those participants that are transitioning from Aim 1 to Aim 2 within 3 months of having completed 
Aim 1, participants will first be consented and if they meet inclusion/exclusion criteria, participants will 
continue on to the remaining procedures of the visits.
All participants will be asked to not take their morning opioid dose. All participants will at one of their 3 
imaging visits receive each of three possible interventions (placebo + placebo, (their) opioid+ 
placebo, or DA+NSAID).
The procedures done at each visit are presented in detail below. To summarize, participants 
complete a series of surveys and procedures enumerated below while being monitored hourly for 
changes in both pain and behavioral changes consistent with waning opioid effects utilizing the Pain 
and Craving Index instrument and the Subjective Opiate Withdrawal Scale (SOWS). After the imaging 
they will be randomized and receive their first treatment period medication, provided by the pharmacy 
as detailed elsewhere. They will then complete a similar set of surveys and procedures as previously  
done and have a second brain scan. Following that scan, they will receive their second treatment 
period medication  and be discharged. The same set of steps outlined above are done at each  visit.
Between visits, all participants will use an eDiary to log their back pain intensity, mood, proper 
medication use, and other information that they may wish to report. Participants will be required to 
complete eDiary ratings between each imaging visit. eDiary entries are immediately transmitted from 
a smartphone device or computer through the Internet to a secure web site, downloaded daily to 
assess compliance, and stored  in a second secure server. Our group has been using such an eDiary 
for about 2 years and this process has been very effective. If needed, participants can also complete 
their eDiary ratings on paper.
6.3 Details of Aim 2 Visit Activities and Procedures
Activities at Screening Visit (~2-3 hours)(if applicable):

Informed Consent.

Demographics.

General medical history and medications.

W-9

Questionnaires in REDCap (all or only a subset to be determined):
o NRS
o
BDI
o
SF-12 Health Survey
o
SFMPQ
o
ODI
o
MAIA
o
Promis57 Survey
o
PDQ
o
CPAQ
o
PASS
o
PSQ
o
ERQ
o
ACS
o
eACS
o
FFMQ
o
NEOFFI
o
LOT
o
LAQ
o
PANAS
o
PCS
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o
COMM

Height and weight

Seated vital signs (temperature, blood pressure, respiration, pulse) measured.

Urine toxicology screen.

Physical Exam (if needed)

Urine pregnancy test for all women of child bearing potential.

Blood collection.(Comprehensive Chemistry Panel, CBC w/ diff)

MRI safety questionnaire.

Set up eDiary
Participants will complete the following procedures at the first imaging visit:
The below will only be done at the first visit or if otherwise deemed necessary:

Read, discuss, and sign this consent form.

W-9
Participants will complete these procedures at each of the imaging visits (~8-9 hours):

Asked to not take their morning opioid medication before coming for this visit

Answer the following Pain and Craving Index questions (completed once before each imaging 
visit and a subset collected once per hour during each imaging visit)
o
“Over the past 24 hours, how strong was your urge to take more opioid medication than 
prescribed?”
o
“Over the past 1 hour, how much did your mood or anxiety level affect any urge to take 
more opioid medication?”
o
“Over the past 1 hour, how often have you found yourself thinking about your next opioid 
dose?”
o
Over the past 1 hour, how much have you craved the medication?”
o
“Over the past 1 hour, what has been your average pain level?”
o
“What is your pain rating now?”

Asked to rate their current mood (once before each imaging visit, as well as once per hour during 
each imaging visit)

Asked to complete SOWS questionnaire to monitor symptoms of opiate withdrawal (hourly)
Answer questionnaires in REDCap regarding their pain, mood, thoughts and feelings (some or all 
of the following): PainDetect
COWS
SFMPQ
NRS
PANAS
PCS
SOWS

Collect blood and urine sample

Psychophysics thermal stimuli

Receive treatment dose 1

Answer questions on pain and craving (completed once per hour)

Answer questionnaires in REDCap regarding their pain, mood, thoughts and feelings (some or all 
of the following):
COWS
SFMPQ
NRS
PANAS
PCS
SOWS
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
MRI scan

Collect blood sample

Psychophysics thermal stimuli

Receive treatment dose 2

Discharge
Below is a reiteration of these activities.  Please note that questionnaires and blood draw can happen 
before or after the MRI brain scan.
Individuals who are allergic or cannot tolerate naproxen or l-dopa may still be enrolled but will have only 
2 imaging visits, receiving either opioid or placebo at each visit based on their treatment allocation.  All 
other procedures will be identical.
6.4 Brain Imaging Procedures
Brain data collection and analysis procedures and software are all in place. All brain scans will be done   
on Trio Prisma 3T multichannel scanners (NU or AbilityLab), using HCP matched parameters 120. Our data 
collection rate for this proposal is thus highly feasible, especially since half the data will come from Baliki’s 
lab.
T1-MRI, DTI-MRI, resting state fMRI and ASL will be performed as described (Baliki M, 2012) 
(Mansour A, 2013) at all imaging visits, with pulse and respiration rates obtained during the scans.
All brain imaging is done on two 3.0 T Siemens Trio whole-body MRI scanner with echo- planar 
imaging (EPI) capability and using a 64 channels head-coil. Both scanners are dedicated for 
research and shared between 15 NIH funded research groups. The university has guaranteed us 
access to these magnets for the next 5 years. The magnets are managed by Radiology 
Department and are fully staffed and equipped. They are core human imaging facilities of NU. 
Their signal-to- noise ratio is excellent and they have produced very nice results over the last 5 
years of operation, and >100 publications.
We will acquire four different types of brain images:
Anatomical T1-MRI (high resolution anatomical magnetic resonance imaging): voxel size = 1 
×1
× 1 mm, repetition time = 2.3 s, echo time = 2.4 ms, flip angle = 9°, in-plane matrix resolution =256 
× 256; 176 slices, field of view = 256 mm.
Resting state fMRI (functional MRI): multi-slice T2*-weighted echo-planar images with repetition 
time = 555 ms, echo time = 22 ms, flip angle = 47°, number of volumes = 1110, slice thickness
= 2 mm, voxel resolution = 2 x 2 x 2 (mm). The slices are covering the whole brain from the 
cerebellum to the vertex.
DTI-MRI (diffusion tensor imaging): diffusion weighted images are acquired along 30 and 64 
isotropic directions using b values of 700 and 2000 s × mm-2, respectively. Field of view=1044 x 
1044, repetition time = 3.5 s, echo time = 92 ms, flig angle = 90. .
ASL (arterial spin labeling): The ASL sequence applies a pseudo-continuous label scheme to 
temporarily label or change the magnetic properties of the flowing blood spins. A “label” image with 
altered blood signal is acquired with a 3-dimensional readout method that facilitates removal of 
background tissue signal using appropriate radiofrequency pulses. A “control” image where the 
magnetic properties of blood spins are not altered is also acquired. Subtraction of the label image 
from the control image further removes non-perfusion related signal and generates a perfusion 
map that can be converted to physiological units (mL/100 g tissue/minute) based on published 
quantification models. Six alternating pairs of control and label images are acquired for signal 
averaging, which reduces noise.
Brain imaging data analysis is done on free-share software including FSL, SPM, FreeSurfer, Caret, 
MRIcron as well as ad-hoc routines written in Matlab, C++, Pearl, Awk. The university maintains a 
user contract for Matlab and other software that we use routinely. We have a dedicated server for 
brain imaging data analysis. This is a 23 TByte data management system and with large number 
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of processors, which runs on Linux. This server is our main brain imaging data storage and 
processing system. It is accessible through Internet, and all data processing is performed on it, 
mainly by remote access.
6.5 Laboratory Procedures/ Evaluations
Baseline laboratory values will be collected for determination of inclusion/exclusion criteria and to assess 
safety and also will be entered into the study database. Repeat laboratory testing will only be done if there 
is a clinical basis for further testing. Blood and urine samples will be collected at the first study visit. Blood 
samples will be collected at each visit. Urine pregnancy tests will be processed before any imaging visits. 
Blood samples will be processed through Pathology Laboratory at NMH, 251 E. Huron St., Chicago, IL 
60611. All results will be faxed to the study doctor for review before participants begin study medications.
Samples will not be frozen nor stored for long-term or future use.
Screening laboratory evaluations will include complete blood count and differential, urine screen for 
pregnancy and illicit drug use, and a chemistry panel (16 tests that assess liver and kidney function and 
electrolyte balance.)
6.6 Surveys and Questionnaires
Questionnaire tools that we plan on using include health assessment, pain and mood related 
characteristics, personality traits, and opioid use and abuse related tools. They are all validated measures and 
show fairly high sensitivity and specificity. Health is assessed only at the first visit.  Pain related measures, 
Opioid use and disuse measures, and personality questionnaires will be collected throughout the study but 
not necessary at all visits.
Personal Health History (PHH): This general questionnaire will assess demographic information 
(sex, age, marital/relationship status, race/ethnicity, socioeconomic data and education), pain history 
(descriptions, diagnostic testing history, and treatment history), general health history (other 
medical/surgical history, concurrent medications, health behaviors, a general symptom checklist, and 
health-care utilization), and work history. The entire questionnaire will be completed at the baseline visit. 
Participants will be asked about any changes to concurrent medications at subsequent visits. History and 
physical examination will be done to confirm diagnosis, inclusion and exclusion criteria and assess overall 
safety.
Numerical Rating Scale (NRS): is an 11-point numerical rating scale used to measure pain intensity.
McGill Pain Questionnaire - Short Form (MPQ): is a pain measure, which permits separation of 
sensory and affective components of pain, as well as a total score.
PainDETECT: A 12-item self-report instrument that assesses neuropathic pain properties.
Positive and Negative Affect Schedule (PANAS): is a 20-item self-report instrument that measures 
positive and negative mood states.
Pain Catastrophizing Scale (PCS): The PCS is a 13-item instrument. It asks participants to reflect 
on past painful experiences, and to indicate the degree to which they experienced each of 13 
thoughts or feelings when experiencing pain.
Subjective Opioid Withdrawal Scale (SOWS): Contains 16 symptoms which the subject rates in 
intensity.
Clinical Opiate Withdrawal Scale (COWS): This is an 11 item scale administered by the staff. It 
assesses objective signs of withdrawal symptoms.
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Current Opioid Misuse Measure (COMM): This is a 17-item self-report measure of risk for aberrant 
medication related behavior among persons with chronic pain who are prescribed opioids for pain.
State Prescription Monitoring Program (DMP): This information is collected from the clinic where a 
given patient was recruited from. Illinois Prescription Monitoring Program (PMP). The PMP is an 
electronic tool that collects information on controlled substance prescriptions, schedules II, III, IV 
and V. This data is reported on a daily basis by retail pharmacies dispensing in Illinois. Prescribers 
and Dispensers of controlled substances are allowed to obtain a user ID and password to query their 
current or prospective patients.
Illinois Prescription Monitoring Program (PMP).
The PMP is an electronic tool that collects information on controlled substance prescriptions, 
schedules II, III, IV and V.
Psychophysics thermal stimuli:
The participant will sit and a thermode (T06, QST Lab, Strasbourg, France) will be placed on the forearm. 
The thermode can deliver heat and cold stimuli. In this study, we will only use heat stimuli. We will deliver 
a series of stimuli until we determine what the participant rates the pain as an 80/100; this will serve as the 
maximum stimulus used for that individual over the course of the experiment. No participant, at any point, 
will receive a stimulus that exceeds this submaximal threshold, and the stimuli used will not be extreme 
enough to cause tissue damage (i.e., all stimuli will be between 30°C and 50°C for short durations, inclusive 
of the extremes; this represents the stimulator’s limits). Finally, the participant can withdraw/stop the 
stimulus at any time during the experiment.
Experimental stimuli will be defined relative to experimentally obtained participant-specific pain thresholds 
or device capabilities (e.g., the device is limited to temperatures ≤ 50°C), using whichever is less extreme. 
We will deliver 10-minute stimulus trains, each containing 3-4 stimuli with 45 sec—2 minutes between each 
stimulus. There will be 10 minutes rest between each stimulus train. There will be a total of 2 stimulus trains 
before study treatment is administered and 2 stimulus trains after study treatment is administered. The 
participant will be asked to rate their pain using an electronic visual analog scale (eVAS). These stimuli will 
not exceed 80% of a person’s maximum—the participant will not be exposed to this 8/10 pain for more than 
1-minute at a time, totaling about 30% of each 10-minute stimulus train. Note, most participants will not be 
exposed to an 8/0; i.e., most ratings will be lower since our calibration protocol produces conservative 
estimates. Each stimulus train will last approximately 10 minutes. The entire duration of the experiment 
should not take longer than 1.5 hours.
Chronic Pain Acceptance Questionnaire (CPAQ): A 20-item questionnaire measuring the effort 
participants put into either actively controlling their pain or passively accepting their pain.
Emotional Regulation Questionnaire (ERQ): A 10-item questionnaire measuring two kinds of 
strategies people use to control their positive and negative emotions.
Attentional Control Scale (ACS): A 20-item questionnaire assessing the voluntary control of attention 
during a variety of situations.
Emotional Attentional Control Scale (eACS): An 18-item questionnaire assessing the voluntary 
control of attention during emotionally demanding situations, which could include pain.
Five Facets of Mindfulness Questionnaire (FFMQ): A 39-item questionnaire measuring the five main 
components of mindfulness—observing, describing, acting with awareness, non-judging of inner 
experience, and non-reactivity to inner experience—as a skill set.
NEO Five Factor Inventory (NEO-FFI): A 60-item questionnaire measuring participants’ scores on 
the personality dimensions of extraversion, agreeableness, conscientiousness, neuroticism, and openness.
Life Orientation Test-Revised (LOT-R): A 10-item questionnaire measuring dispositional optimism.
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Loss Aversion Questionnaire (LAQ): A 20-item questionnaire measuring how sensitive participants 
are to a wide variety of potential “losses” in their lives.
Pain and Craving Index: A 6-item questionnaire used to measure pain and craving intensity.
Other information regarding procedures:
Definition of CBP+O vs CBP+OUD vs CBP-O. Dr. Wasan, a co-investigator developed the DMI, which is an 
accepted method for determining adherence/nonadherence (use disorder) to opioid therapy tested in 
multiple clinical trials115,116 . The DMI triangulates three domains: patient self-report using the Current Opioid 
Misuse Measure (COMM), provider assessment of use disorder using the Addiction Behaviors Checklist 
(ABC) and the state Prescription Monitoring Program (DMP), and UDT results to determine adherence to 
opioids. The DMI is positive if use disorder is found on any domain. The DMI has been able to distinguish 
between a mild to moderate OUD and severe OUD .The Subjective Opiate Withdrawal Scale (SOWS) will 
be used to describe psychological and physical withdrawal symptoms. These domains will determine 
whether a participant presents with use disorder.
Morphine estimate equivalence (MEE) will be calculated for total use, blood levels, and specific dose 
ingested at scan time. There is clear evidence of inter-individual variability of opiate efficacy (PK-PD) in 
different clinical responses among patients118. Still, MEE allows us to estimate the dose of morphine, based 
on the dose of opioid use, route of administration, and conversion ratio. There are multiple calculators 
available, we will use119.
eDiary. Documenting pain and drug craving in the natural setting of everyday life reduces the bias of 
patients attempting to “please the caregiver” and better characterizes these parameters. We have tested 
such a tool in 120 CBP patients and observed very high compliance. We will adapt this app, using validated 
queries103.
7. DATA AND SPECIMEN BANKING
We foresee that the brain imaging data and related PROs may be used in future studies, either by us or 
when we make this data available on OpenPain for use by other researchers (Apkarian, 2014). In all such 
cases all data will be fully anonymized prior to their availability for future use by investigators outside of 
Apkarian’s lab.
Stored blood specimens used to collect MEE will be kept within frozen lab storage up until 5 years after  
end of study. Specimens will be destroyed after 5 years. 
8. SHARING RESULTS WITH PARTICIPANTS
Copies of lab results may be provided to subjects who request these.
9. STUDY TIMELINE
For Aim 2, we expect to initiate recruitment in October, 2019 and complete enrollment by June, 2022. This 
will require our enrolling approximately 1-2 participants/month in each of the CBP+O & CBP+ OUD groups.
10.
INCLUSION AND EXCLUSION CRITERIA
Inclusion Criteria for all patients:
1.
History of chronic localized pain  for a minimum of 6 months daily (prior to screening), 
meeting the Quebec Task Force Classification System symptom categories I-III;
2.
Male or female, age equal or greater than 18 years, with no racial/ethnic restrictions;
3.
Must be able to read and speak English and be willing to read and understand 
instructions as well as questionnaires
4.
Must be in generally stable health;
5.
Must sign an informed consent document after a complete explanation of the study 
documenting that they understand the purpose of the study, procedures to be 
undertaken, possible benefits and potential risks, and are willing to participate;
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6.
Must be willing to complete daily smartphone/computer eDiary ratings;
7.
Must be on regular opioid therapy for at least 3 months prior to randomization, which will 
be up to the clinical investigator’s decision
8.
Must be on a short acting opioid therapy (anticipated duration of action < 6 hours)

As defined by Massachusetts Health and Human Services, short-acting opioids 
include but are not limited to the following medications:

Acetaminophen/codeine

Codeine

Fentanyl tablets

Hydrocodone/acetaminophen

Hydrocodone/ibuprofe n

Hydromorphone

Morphine

Oxycodone/acetamino phen

Tramadol

This will also be left up to the discretion of the clinical PI 
Exclusion Criteria for all patients:
1.
Chronic localized pain associated with any systemic signs or symptoms, e.g., fever, chills;
2.
Any clinically significant comorbid chronic pain or neurological conditions including 
CRPS, Alzheimer’s disease and other dementia-related conditions;
3.
Use of therapeutic doses of antidepressant medications at unstable doses (i.e., tricyclic 
depressants, SSRIs, SNRIs; low doses used for sleep may be allowed);
4.
Any clinically significant cardiovascular, endocrine, hepatic, renal, pulmonary, 
gastrointestinal, neurologic, malignant, metabolic, psychiatric, or other condition that, in 
the judgement of the Investigator, would pose a safety risk, or cause subject to be 
unsuitable for participation and/or unable to complete the study procedures.
5.
Uncontrolled hypertension;
6.
Clinically significant renal insufficiency;(correlated creatinine clearance < 40mL/min or 
serum creatinine ≥2)
7.
Subject unable or unwilling to follow requirements and instructions;;
8.
Evidence of poor prior treatment compliance;;
9.
Intra-axial implants (e.g. spinal cord stimulators or pumps);
10. Contraindications for undergoing MRI, i.e : metallic implants, brain or skull abnormalities, 
tattoos on large body parts, and claustrophobia;
11. Pregnancy, or inability to use an effective form of contraception in women of child-bearing 
age;
12. An established diagnosis of diabetes (type 1 or type 2)
13. Lactose intolerance
14. Use of a patch or long acting opioid therapy (e.g. anticipated duration of action > 6 hours)
11. RECRUITMENT METHODS
Aim 2:
We plan to recruit 80 individuals (40 CBP+O & 40 CBP+OUD). Those participants from Aim 1 that are 
taking short-acting opioid therapy will be given the option to participate in Aim 2. We expect to complete 
50% recruitment for Aim 1 by year 2.5. All recruitment is anticipated to be finalized by the middle of year 
4.  
We anticipate screening over 500 individuals (to enroll 250 participants) with chronic back pain over 4 
years, all drawn from the Chicago metropolitan area. There are no racial, ethnic or gender restrictions 
and no upper age limit. It is anticipated that the study population will generally reflect that of Chicago. Our 
experience from previous chronic back pain studies provides us reassurance that we will be able to 
identify this number of individuals required to be screened and that we will achieve a diverse participant 
cohort.
Participants will be drawn from two major pools of individuals: those being seen within the Northwestern 
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Medicine (NM) healthcare system and those being seen the Shirley Ryan Ability Lab, with approximately 
50% of participants coming from each source. If additional recruitment is necessary, we will utilize our 
recruitment database and local recruitment efforts such as print ads and social media to reach out to the 
local community.
NM maintains an electronic data warehouse (EDW) that contains and makes accessible for researchers 
the electronic medical records of all individuals who are seen by clinicians within the system and who 
provide consent. Access is obtained through requests based on specific ICD-10 codes and providers. 
We have used this system since its inception several years ago with great success, allowing us to identify 
and contact a large number of people with well-defined illnesses, including back pain. We have 
supplemented this approach by direct involvement with specific practitioners who deal with large numbers 
of chronic back pain patients, primarily with the departments of orthopedic surgery, neurosurgery and 
anesthesiology. We have on-going relationships with specific clinicians and research coordinators within 
these groups to assist in the identification and recruitment of specific populations. The combination of the 
EDW referrals and the direct physician referrals assures a high number of potential candidates with well- 
defined backgrounds and illnesses for studies. We have utilized both these approaches in our past as 
well as on-going studies in patients with CBP and are confident that these referral sources will continue to 
be productive.
Media Advertising: Advertising in the media (newspaper and radio) has proven to be extremely effective 
in identifying people with low back pain in our previous longitudinal study. Expertise in media placement 
as well as use of experienced phone personnel is a core competency within our research group. A 
recruitment plan specific for this study will be developed and implemented by the recruitment division 
staff, working in close conjunction with the investigators and other study personnel. This methodology in 
the past has yielded 20-30% of participants for trials of this sort.
Online Advertising: Advertising using online resources (including but not limited to social media, e.g., 
Facebook and Twitter, www.craigslist.com, online newspaper classifieds, and websites for people who 
work with or have low back pain or related conditions has been a fruitful approach to identifying individuals 
with CBP for our previous and on-going CBP research. As with traditional media advertising, we are able 
to control when and how often we place these advertisements to make maximum use of our staff’s time. 
This approach has generated 20-30% of participants for trials of this sort in the past, and this percentage 
is growing with traditional media advertising decreasing over time.
Community Advertising: Given the high reliance on public transportation in the Chicago area, advertising 
in bus, train, and rail stations/facilities reaches a large number of citizens from broad socioeconomic 
backgrounds. Ridership reports indicate the Chicago Transit Authority ridership exceeds 2 million bus, 
train, and rail rides each day. Even short-term advertising in these venues has repeatedly resulted in 
large numbers of calls that continue to come in over long periods of time. In addition, coffee shops and 
libraries are opportunities to tap into diverse communities. As with the above approaches, this 
methodology will be expected to yield approximately 1-20% of the participants for this trial.
We anticipate a population that will roughly approximate the Chicago area with regard to ethnicity and 
race (approximately 25% Hispanic; 30% African-American, 40% non-Hispanic White, 5% Asian).
Materials that will be used, will be added as a separate modification and will receive IRB approval prior 
to implementation.
All recruitment materials will be submitted as a modification to the IRB, and approved prior to being 
implemented.
12. COMPENSATION FOR PARTICIPATION IN RESEARCH ACTIVITIES
Aim 2: Subjects will be paid $75.00 for visits 1 and 2 and will be paid $150.00 for study visit 3. Subjects will 
be  paid via PNC card, cash or check for Visits 1 through 3. For any subjects that are required to complete 
a screening visit prior to the study visits, they will be compensated $25 in cash. For any subjects that require 
transportation, it will be provided.  And for any subject that requires a parking voucher, $5.00 will be 
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deducted from the total payment for the visit to cover the cost of the voucher.
Payment will be prorated based on visit completion. If a participant does not complete a study visit in its 
entirety, they will receive only $10.In addition, participants will receive $0.25 per value eDiary entry recorded 
throughout the study as instructed.
Lunch may be provided to subjects. In the event it is a $20.00 limit will be instituted.
13. WITHDRAWAL OF PARTICIPANTS
Subjects may be withdrawn from the research study if:
-
They fail to follow instructions
-
The Investigator decides it would not be in the subject’s best interest to finish the study
-
The Investigator, NIH or FDA decides to end the study for either medical or administrative reasons
There are no procedures for subjects who decide to withdrawal from the research.
14. RISKS TO PARTICIPANTS
14.1 Risks from Procedures 
MRI scans
The MR environment is hazardous and only people properly trained regarding safety procedures are 
allowed to use the facility. There is risk of claustrophobia and anxiety involved with the fMRI scanning 
procedure; subjects will be queried about any concerns they may have prior to testing. Subjects must 
consent to tolerate being in the scanner, which involves the potentially uncomfortable experience of lying in 
a relatively confined space with minimal head and body movements for up to 60 minutes at a time. In this 
time period, their back pain may become worse. Personnel continuously query the subject in the scanner 
as to their level of pain and will discontinue the scan and relieve the subject from the discomfort at any time 
requested. Our routine procedure is to give subjects multiple breaks from scanning, which minimizes fatigue 
and decreases anxiety, resulting in high- quality data. It is possible that the anatomical scans may uncover 
a brain abnormality of which the participant was not aware. In such cases, the participant is removed from 
the study and given appropriate medical advice by  Dr. Schnitzer. The likelihood of this happening is low 
(<1%). Over the last 5 years of doing brain scans in various chronic pain patient populations, the main 
limiting factor has been claustrophobia. Although we query subjects on this routinely, participants often are 
surprised at how anxious they feel in the scanner and simply cannot tolerate it. Otherwise, chronic pain 
patients are usually enthusiastic in participating in these trials.
Psychophysics thermal stimuli
Physically, the thermal stimuli applied may cause some temporary pain or discomfort. However, there 
is minimal risk that the stimuli will lead to actual tissue damage (e.g. burn or broken skin). In the event 
there is injury, we will provide first aid as necessary.
Questionnaire Risks
Although the majority of participants will find the questionnaires to be harmless, mundane, or
possibly interesting, there is always a possibility that some of the questions may be sensitive in nature and 
may make them uncomfortable (particularly those asking about mood or personality). In the past, we have 
added an option into our REDCap database that allows participants to skip questions they don’t feel 
comfortable answering, so they will never be forced to answer something they do not want to. We have 
found that most people still answer all questions fully despite having this optional button and that most 
participants have no missing data. Therefore, we will continue to use this option in the proposed study.
Dr. Griffith, a licensed clinical psychologist, will be available to consult about any concerns that 
patients have about their mental health, including referrals to appropriate providers. All participants will be 
given a list of referral sources in case they wish to seek mental healthcare, and participants will be invited 
to contact the research team with questions about getting connected with appropriate healthcare.
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Additionally, the clinical research managers are trained in suicide prevention techniques should any 
immediate need arise during a study visit or follow-up.
Phlebotomy risk
The possibility exists for pain, ecchymosis and rarely localized infection as a consequence of 
phlebotomy. These will be minimized by careful aseptic technique and involvement of experienced 
phlebotomists.
Delay of opioids risk
While patients will only delay their opioid medication briefly, there is potential risk in doing so. To ensure 
that patient safety is being upheld, the clinical co-investigator will be on call to respond to any patient needs. 
This may also lead to a brief worsening of back pain.
14.2 Risks from Medications 
Carbidopa/Levodopa
Carbidopa/Levodopa is a therapy that combines the dopamine agonists Levodopa and Carbidopa. 
The combination aims at increasing the levels of dopamine in the brain while preventing any similar 
increase in the rest of the body, hence minimizing side effects. The list of adverse events noted below 
derives from the package insert for Carbidopa/Levodopa and was a consequence of AEs reported in 
clinical trials of individuals with Parkinson’s disease who have depleted brain dopamine levels. The most 
common side effects (prevalence ≥ 1.5%) of Carbidopa/Levodopa are shown below and information 
from the package insert which lists all reported side effects, regardless of prevalence, follows (Sinemet 
CR, 2011).
Adverse 
Experience
Carbidopa/Levod op a 
(n = 524)
Dyskinesia
12.2%
Nausea
5.7%
Hallucinations
3.2%
Confusion
2.3%
Dizziness
2.3%
Urinary Tract
2.3%
As noted, the most common adverse reactions reported with Carbidopa/Levodopa have included  dyskinesias, 
Infection
Headache
1.9%
Vomiting
1.9%
Constipation
1.5%
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such as choreiform, dystonic and other involuntary movements, and nausea.
The following other adverse reactions have been reported with Carbidopa/Levodopa:

Body as a Whole: chest pain, asthenia.

Cardiovascular: cardiac irregularities, hypotension, orthostatic effects including orthostatic 
hypotension, hypertension, syncope, phlebitis, palpitation.

Gastrointestinal: dark saliva, gastrointestinal bleeding, development of duodenal ulcer, 
anorexia, vomiting, diarrhea, constipation, dyspepsia, dry mouth, taste alterations.

Hematologic: agranulocytosis, hemolytic and non-hemolytic anemia, thrombocytopenia, 
leukopenia.

Hypersensitivity: angioedema, urticaria, pruritus, Henoch-Schonlein purpura, bullous 
lesions (including pemphigus-like reactions).

Musculoskeletal: back pain, shoulder pain, muscle cramps.

Nervous System/Psychiatric: psychotic episodes including delusions, hallucinations, and 
paranoid ideation, neuroleptic malignant syndrome, bradykinetic episodes ("on-off" 
phenomenon), confusion, agitation, dizziness, somnolence, dream abnormalities 
including nightmares, insomnia, paresthesia, headache, depression with or without 
development of suicidal tendencies, dementia, pathological gambling, increased libido 
including hypersexuality, impulse control symptoms. Convulsions also have occurred; 
however, a causal relationship with Carbidopa/Levodopa has not been established.

Respiratory: dyspnea, upper respiratory infection.

Skin: rash, increased sweating, alopecia, dark sweat.

Urogenital: urinary tract infection, urinary frequency, dark urine.

Laboratory Tests: decreased hemoglobin and hematocrit; abnormalities in alkaline 
phosphatase, SGOT (AST), SGPT (ALT), lactic dehydrogenase, bilirubin, blood urea 
nitrogen (BUN), Coombs test; elevated serum glucose; white blood cells, bacteria, and 
blood in the urine.
Other adverse reactions that have been reported with Levodopa alone and with various
Carbidopa/Levodopa formulations, are:

Body as a Whole: abdominal pain and distress, fatigue

Cardiovascular: myocardial infarction.

Gastrointestinal: gastrointestinal pain, dysphagia, sialorrhea, flatulence, bruxism, burning 
sensation of the tongue, heartburn, hiccups.

Metabolic: edema, weight gain, weight loss.

Musculoskeletal: leg pain.

Nervous System/Psychiatric: ataxia, extrapyramidal disorder, falling, anxiety, gait 
abnormalities, nervousness, decreased mental acuity, memory impairment, 
disorientation, euphoria, blepharospasm (which may be taken as an early sign of excess 
dosage; consideration of dosage reduction may be made at this time), trismus, increased 
tremor, numbness, muscle twitching, activation of latent Horner's syndrome, peripheral 
neuropathy.
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
Respiratory: pharyngeal pain, cough.

Skin: malignant melanoma, flushing.

Special Senses: oculogyric crises, diplopia, blurred vision, dilated pupils.

Urogenital: urinary retention, urinary incontinence, priapism.

Miscellaneous: bizarre breathing patterns, faintness, hoarseness, malaise, hot flashes, 
sense of stimulation.

Laboratory Tests: decreased white blood cell count and serum potassium; increased 
serum creatinine and uric acid; protein and glucose in urine.
Naproxen
A dose of Naproxen 500mg will be administered alongside the carbidopa/levodopa administration once per 
patient. Participants with uncontrolled hypertension, history of recent myocardial infarction, peptic ulcer 
disease, renal disease or history of allergies to NSAID medication will be excluded.
Adverse reactions reported in controlled clinical trials in 960 patients treated for rheumatoid arthritis or 
osteoarthritis are listed below. In general, reactions in patients treated chronically were reported 2 to 10 
times more frequently than they were in short- term studies in the 962 patients treated for mild to moderate 
pain or for dysmenorrhea. The most frequent complaints reported related to the gastrointestinal tract.
A clinical study found gastrointestinal reactions to be more frequent and more severe in rheumatoid arthritis 
patients taking daily doses of 1500 mg Naproxen compared to those taking 750 mg Naproxen.
In controlled clinical trials with about 80 pediatric patients and in well-monitored, open- label studies with 
about 400 pediatric patients with juvenile arthritis treated with Naproxen, the incidence of rash and prolonged 
bleeding times were increased, the incidence of gastrointestinal and central nervous system reactions were 
about the same, and the incidence of other reactions were lower in pediatric patients than in adults.
In patients taking Naproxen in clinical trials, the most frequently reported adverse experiences in 
approximately 1 to 10% of patients are:

Gastrointestinal (GI) Experiences, including: heartburn*, abdominal pain*, nausea*, 
constipation*, diarrhea, dyspepsia, stomatitis

Central Nervous System: headache*, dizziness*, drowsiness*, lightheadedness, vertigo 
Dermatologic: pruritus (itching)*, skin eruptions*, ecchymoses*, sweating, purpura Special 
Senses: tinnitus*, visual disturbances, hearing disturbances

Cardiovascular: edema*, palpitations

General: dyspnea*, thirst

*Incidence of reported reaction between 3% and 9%. Those reactions occurring in 
less than 3% of the patients are unmarked.
In patients taking NSAIDs, the following adverse experiences have also been reported in 
approximately 1 to 10% of patients.

Gastrointestinal (GI) Experiences, including: flatulence, gross bleeding/perforation, GI 
ulcers (gastric/duodenal), vomiting
General: abnormal renal function, anemia, elevated liver enzymes, increased bleeding time, 
rashes
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The following are additional adverse experiences reported in <1% of patients taking 
Naproxen during clinical trials and through post-marketing reports. Those adverse 
reactions observed through post-marketing reports are italicized.

Body as a Whole: anaphylactoid reactions, angioneurotic edema, menstrual disorders, 
pyrexia (chills and fever)

Cardiovascular: congestive heart failure, vasculitis

Gastrointestinal: gastrointestinal bleeding and/or perforation, hematemesis, jaundice, pancreatitis, 
vomiting, colitis, abnormal liver function tests, nonpeptic gastrointestinal ulceration, ulcerative 
stomatitis

Hemic and Lymphatic: eosinophilia, leucopenia, melena, thrombocytopenia, agranulocytosis, 
granulocytopenia, hemolytic anemia, aplastic anemia

Metabolic and Nutritional: hyperglycemia, hypoglycemia

Nervous System: inability to concentrate, depression, dream abnormalities, insomnia, malaise, 
myalgia, muscle weakness, aseptic meningitis, cognitive dysfunction

Respiratory: eosinophilic pneumonitis

Dermatologic: alopecia, urticaria, skin rashes, toxic epidermal necrolysis, erythema multiforme, 
Stevens-Johnson syndrome, photosensitive dermatitis, photosensitivity reactions, including rare 
cases resembling porphyria cutanea tarda (pseudoporphyria) or epidermolysis bullosa. If skin 
fragility, blistering or other symptoms suggestive of pseudoporphyria occur, treatment should be 
discontinued and the patient monitored.

Special Senses: hearing impairment

Urogenital: glomerular nephritis, hematuria, hyperkalemia, interstitial nephritis, nephrotic 
syndrome, renal disease, renal failure, renal papillary necrosis
In patients taking NSAIDs, the following adverse experiences have also been reported in
<1% of patients.

Body as a Whole: fever, infection, sepsis, anaphylactic reactions, appetite changes, death

Cardiovascular: hypertension, tachycardia, syncope, arrhythmia, hypotension, 
myocardial infarction

Gastrointestinal: dry mouth, esophagitis, gastric/peptic ulcers, gastritis, glossitis, hepatitis, 
eructation, liver failure

Hemic and Lymphatic: rectal bleeding, lymphadenopathy, pancytopenia

Metabolic and Nutritional: weight changes

Nervous System: anxiety, asthenia, confusion, nervousness, paresthesia, somnolence, tremors, 
convulsions, coma, hallucinations

Respiratory: asthma, respiratory depression, pneumonia
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
Dermatologic: exfoliative dermatisis

Special Senses: blurred vision, conjunctivitis Urogenital: cystitis, dysuria, oliguria/polyuria, 
proteinuria
14.3
Emergency care
If participants need emergency medical care, they will be instructed to go to the closest emergency room 
and inform the healthcare provider that they are enrolled in this study. If the need is not emergent, they 
will be asked to come to the clinic to be seen by Dr. Schnitzer. Participants will be responsible for the 
cost of any emergency or non-emergency medical care that may arise during or as  a consequence of 
their involvement in this study.
14.4
Protections against Risk General
The primary protection will be the enrollment only of eligible subjects, i.e., subjects meeting all inclusion 
and exclusion criteria. Individuals having clearly identified causes of chronic localized pain will be 
carefully excluded. In addition, individuals who cannot tolerate the confinement of an MRI scanner and 
those who may not be able to be scanned because of implanted metal devices will be excluded. 
Following treatment administration, safety monitoring for non-serious and serious adverse events is 
planned at each study visit until the completion of the trial. All adverse events will be collected and 
reviewed by the clinical lead investigator and principal investigator on a monthly basis. A chronological 
log of all SAE’s will be maintained and reviewed by the PI every month, as well. Privacy and 
confidentiality will be maintained by the use of allocation numbers throughout the study, with the master 
study list (excluding randomization codes) being maintained by the PI with availability limited to those 
study personnel who have a documented need for this information.
In addition to the PI’s responsibility for oversight, study oversight will be under the direction of an 
Independent Safety Monitor (ISM), who has expertise in clinical trials. The ISM is independent of the 
study and will be available in real time to review and recommend appropriate action regarding adverse 
events and other safety issues. Careful monitoring of safety will be undertaken by the study team with 
regular oversight by the clinical investigator and the principal investigator.
Aim2:
Statistical analysis of the data collected will be led by co-investigator Dr. James Griffith.
15.
POTENTIAL BENEFITS TO PARTICIPANTS
There is no direct benefit to subjects.
Taking part in this study may help scientists to better understand more about pain and addictive 
behavior. It will also help scientists to determine if opioid analgesia and opioid addiction have important 
interactions with the brain pathways involved in chronic pain and if in time, exacerbate opioid use 
disorder and diminish opioid analgesic efficacy.
16.
DATA MANAGEMENT AND CONFIDENTIALITY
All analyses will be done blinded.
16.1
Statistical Considerations and Power Analysis:
Our primary comparison is between categories of opioid exposure in CBP. In addition, we will have 
brain- based measures, collected once in Aim 1, and three times in Aim 2. In the discovery phase, we 
will perform whole-brain contrasts (with proper correction for multiple comparisons) where we will have 
25-40 subjects per group (Aim 1). Power considerations for Aim 2 will be finalized after initiation of Aim 
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1; however, with 30 subjects per group but with 6 observations per subject contrasted to each other; a 
within-subject repeat contrasted across groups will result in more power than in Aim 1. This provides 
power >80% for detecting effects sizes of 0.75 or greater, assuming alpha = 0.01 (two-tailed). Our 
published whole-brain contrasts have been based on average n = 25 subjects per group. Comparison 
between groupings for behavioral outcomes should also be able to detect effect sizes of 1.0 with n=25 
per group, with power approximately 80% assuming alpha = 0.01 (two-tailed). We will recruit a diverse 
population with comorbidities and likely high variability, and we plan on an aggressive brain- motion 
correction given recent reports of its large effect on network properties 121, and also because there are 
concerns that fMRI statistics have been inflated in the past 122 (note: we will strictly use permutation 
testing to ensure statistics are precise). Only a minimal set of results will be tested for replication in the 
validation data.
Biomarkers for resilience are brain parameters that differentiate CBP+OUD and CBP+O, and do not 
change between opioid withdrawal and re-exposure. For model building, our power analyses indicate that 
our sample size will be adequate, even after accounting for missing data. If we approach the analyses by 
classifying people into resilient/vulnerable (~50% expected in each group), statistical power would be 
adequate; assuming overall N = 80, an odds ratio of 2.0 as the effect size for a target predictor (which 
would be clinically significant) with an overlap of other predictors of R2 = .09 (a medium-sized relationship 
with other predictors), and a two-tailed Type I error rate of .05, power would exceed 85%. These power 
analyses are based on a binary classification of the dependent variable, but we are also familiar with 
methods that treat the dependent variable as continuous (e.g., mixed modeling, latent growth curve 
modeling 123), techniques that increase statistical power. For model validation, algorithms derived will be 
applied to new cases. For all analyses, cases with and without missing data will be compared, and 
multiple imputation strategies will be explored.
16.2
Data Handling and Record Keeping
The investigators are responsible for ensuring the accuracy, completeness, legibility, and timeliness of 
the data reported. All source documents should be completed in a neat, legible manner to ensure accurate 
interpretation of data. The investigators will maintain adequate case histories of study participants, 
including accurate CRFs, and source documentation. The records will be stored offsite at REEBIE 
storage for 7 years past study completion. After the 7 years, data is destroyed.
16.3
Data Management Responsibilities
Data collection and accurate documentation are the responsibility of the study staff under the supervision 
of the investigator. All source documents and laboratory reports must be reviewed by the study team and 
data entry staff, who will ensure that they are accurate and complete. UPs and AEs must be reviewed by 
the investigator or designee.
16.4
Data Capture Methods
We plan to use REDCap (http://www.project-redcap.org/) as our data management tool. Participant- 
entered data will be collected directly into the REDCap. If needed, the REDCap entered data can be 
printed for paper records. PROs, will not contain any PHI and will be directly entered into REDCap.
Clinical (e.g., medical history and physical examination, pain evaluations) and functional (e.g., brain 
phenotype) entered into REDCap. There will be a source document used to confirm a participant’s 
passing or failing inclusion/exclusion criteria. Other data collected by study staff pertaining to the study 
visit will be entered into REDCap. Results of labs and any other documents that are received will be 
stored on paper and electronically in REDCap. Consent forms containing the subject’s signature and date 
will be stored on paper and electronically uploaded to REDCap as well.
16.5
Types of Data
Our research staff will be collecting multiple types of data pertaining to the participants, such as those 
dealing with safety, imaging, and behavioral and medical participant domains. The safety of the 
participant will be initially assessed through obtaining a thorough history and assuring that participants 
meet all the criteria of the inclusion/exclusion checklist, which reviews comorbid illnesses. Safety data will 
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continue to be collected at each contact with participants and recorded in the source documents.
There will not be a separate safety database. Imaging data will be collected during each of the scanning 
visits and will be collected based on well-documented protocols. Behavioral data will be provided through 
selected patient PROs that assess various aspects of pain and overall quality of life. Medical data will be 
collected primarily during physical examinations and from a baseline blood draw, in addition to follow-up 
visits throughout the study. These measurements include BP, heart rate, chemistry panel, CBC, drug 
urine screening, and urine pregnancy screening.
Lab specimens will not be stored for future use. Specimens will be discarded after processing has been 
completed.
16.6
Confidentiality
Study staff will maintain appropriate medical and research records for this study, in compliance with ICH 
E6, Section 4.9 and regulatory and institutional requirements for the protection of confidentiality of 
participants. All source documents pertaining to an individual participant is compiled into a participant 
folder. Each participant folder includes, but is not limited to, records on personal contact information, 
demographic information, physical exam, vital signs, personal health history, researcher comments from 
each visit, PROs, concomitant medication logs, study medication logs, indications of any AEs 
experienced, clinical laboratory results, and ICFs. PROs will be collected directly into REDCap (REDCap 
is the source document), but can be printed and maintained with the participant folder if need be. All 
folders are kept in a locked cabinet, located in a locked room away from all participant activity.
Only study coordinators have access to the locked room and cabinet. These paper charts are also kept 
separate from any hospital records acquired through NMH or the NMFF. Study staff will permit authorized 
representatives of NIH, the NU IRB and defined regulatory agencies to examine (and when required by 
applicable law, to copy) research records for the purposes of quality assurance reviews, audits, and 
evaluation of the study safety, progress and data validity.
All brain imaging data are maintained on a secure server, stored under lock at the NMH hospital server 
banks. Access to these data are password protected, and all brain scan data are anonymized and coded 
prior to being available on the server. Only NUCATS will maintain the lock for the specific subject-to-data 
correspondence, and this information is not anticipated to be used, except in some unusual emergency 
situation (such an event has not arisen in the past >15 years).
17.
PROVISIONS TO MONITOR THE DATA TO ENSURE THE SAFETY OR PARTICIPANTS
The investigator will ensure that this study is conducted in full conformity with the principles set forth in 
The Belmont Report: Ethical Principles and Guidelines for the Protection of Human Participants of 
Research, as drafted by the US National Commission for the Protection of Human Participants of 
Biomedical and Behavioral Research (April 18, 1979) and codified in 45 CFR Part 46 and/or the ICH E6.
In order to monitor the progress of the study and to provide quality control, a number of reports will be 
regularly generated throughout the course of the study. The clinical investigator will have a weekly 
meeting with all study staff to review the status of the study and address issues that have arisen during 
the week. At this meeting, a recruitment and retention report will be presented and discussed. Dates of 
important summary reports (e.g., annual IND report, report to clinical committee, IRB annual renewal, 
etc.) will be highlighted. In general, a draft of any report to be circulated outside the study team will be 
prepared at least one week prior to the deadline for the report needing to be sent in order to provide 
adequate time for review and discussion. It is anticipated that there will be a data review regarding safety 
done semi-annually or more often as requested by the study oversight committee. Outcome data will not 
be reviewed until after database lock, though the integrity and completeness of data will be assessed on 
a semi-annually basis as part of quality assurance activities. The database will not be locked until all data 
fields have been checked and any remaining discrepancies dealt with. Once the database has been 
locked, no further changes will be made and the randomization code can be provided to the study 
statistician.
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17.1
Adverse Event Monitoring
Adverse event data collection and reporting, which are required as part of every clinical trial, are done to 
ensure the safety of subjects enrolled in the studies, as well as those who will enroll in future studies using 
similar agents. Adverse events are reported in a routine manner at scheduled times during a trial. 
Additionally, certain adverse events must be reported in an expedited manner to allow for optimal 
monitoring of patient safety and care.
All patients experiencing an adverse event, regardless of its relationship to study compound/drug, will be 
monitored until:
the adverse event resolves or the symptoms or signs that constitute the adverse event return to 
baseline;
any abnormal laboratory values have returned to baseline;
there is a satisfactory explanation other than the study compound/drug for the changes observed; 
or
death.
The reporting of adverse events, serious adverse events and unanticipated problems will be done 
according to the guidelines of the Northwestern University IRB and the FDA*. As of August 20, 2007, 
Northwestern University IRB requires filing of internal or external adverse events reports, or safety reports 
only if they have been determined by the Principal Investigator to contain a report of unanticipated 
problems involving risks to subjects or others. NU considers unanticipated problems, in general, to 
include any adverse event, incident, experience, or outcome that meets all of the following criteria: (1) 
Unexpected (in terms of nature, severity, or frequency) given: (a) the research procedures that are 
described in the protocol-related documents, such as the IRB-approved research protocol and informed 
consent document; and (b) the characteristics of the subject population being studied. 1. The known or 
foreseeable risk of adverse events associated with the procedures involved in the research that are 
described in: a) the protocol-related documents, such as the IRB-approved research protocol, any 
applicable investigator brochure, and the current IRB-approved informed consent document;
and b) other relevant sources of information, such as product labeling and package inserts; or 2. The 
expected natural progression of any underlying disease, disorder, or condition of the subject(s) 
experiencing the adverse event and the subject's predisposing risk factor profile for the adverse event.
(2)
Related or possibly related to participation in the research (in this guidance document, possibly 
related means there is a reasonable possibility that the incident, experience, or outcome may have been 
caused by the procedures involved in the research); and (3) Suggests that the research places subjects 
or others at a different or greater risk of harm (including physical, psychological, economic, or social harm) 
than was previously known or recognized.
NOTE: The following events are considered a serious adverse event and would place subjects at a greater 
risk of harm:

results in death;

is life-threatening (places the subject at immediate risk of death from the event as it occurred);

results in inpatient hospitalization or prolongation of existing hospitalization;

results in a persistent or significant disability/incapacity;

results in a congenital anomaly/birth defect; or

based upon appropriate medical judgment, may jeopardize the subject’s health and may require 
medical or surgical intervention to prevent one of the other outcomes listed in this definition (examples of 
such events include allergic bronchospasm requiring intensive treatment in the emergency room or at 
home, blood dyscrasias or convulsions that do not result in inpatient hospitalization, or the development 
of drug dependency or drug abuse).
Unanticipated problems involving risks to subjects or others should be reported to the IRB within 10 
working days (unanticipated deaths of subjects enrolled at NU or Affiliates need to be reported within 24 
hours).
All adverse events deemed to be serious, both unexpected and expected, will be reported to the medical 
monitor.
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Unanticipated problems involving risk to volunteers or others, serious adverse events related to 
participation in the study and all volunteer deaths related to participation in the study will be promptly 
reported by phone, by e-mail, or by facsimile to the FDA*.
The medical monitor is required to review all unanticipated problems involving risk to volunteers or others, 
serious adverse events and all volunteer deaths associated with the protocol and provide an unbiased 
written report of the event to the FDA and NIDA. The medical monitor will comment on the outcomes of 
the event or problem and in the case of a serious adverse event or death comment on the relationship to 
participation in the study. The medical monitor will also indicate whether he/she concurs with the details 
of the report provided by the study investigator. Reports for events determined by either the investigator 
or medical monitor to be possibly or definitely related to participation and reports of events resulting in 
death will be promptly forwarded to the FDA and NIDA.
A summary table of adverse events collected will be submitted at least annually to the Northwestern IRB 
and to NIDA.
17.2
Reporting of SAEs
SAEs that are unanticipated, serious, and possibly related to the study intervention will be reported to the 
Independent Monitor, IRB, and NIDA in accordance with requirements.

Anticipated or unrelated SAEs will be handled in a less urgent manner but will be reported to the 
Independent Monitor, IRB, NIDA, and other oversight organizations in accordance with their 
requirements.

Unexpected fatal or life-threatening AEs related to the intervention will be reported to the NIDA 
Program Officer within 7 days.
17.3
Unblinding Procedures
Unblinding the study therapy may be necessary to ensure a subject’s safety. In most cases, the 
unblinding will be part of managing an SAE, and will be reported with the SAE, however, in cases where 
unblinding was not associated with an SAE, such actions should be reported in a timely manner (e.g., 
notification of IRB within 24 hours by phone or fax, followed by a written narrative of the event within 48 
hours.). Otherwise, unblinding will not be done until each phase of the study is complete (that is, when 
Aim 1 is finished running all enrolled participants, we can unblind the data).
17.4
Stopping Rules/Intervention Discontinuation
This study will be stopped prior to completion if there is difficulty in study recruitment or retention that will 
significantly impact the ability to evaluate the study endpoints; (2) any new information becomes available 
during the trial that necessitates stopping the trial; or (3) other situations occur that might warrant stopping 
the trial.
18.
PROVISIONS TO PROTECT THE PRIVACY INTERESTS OF PARTICIPANTS
Please see section below regarding privacy.
19.
COMPENSATION FOR RESEARCH-RELATED INJURY
If a subject is injured as a result of this study (medications, or procedures), they should seek medical 
treatment through their primary care physician or treatment center of choice. They will be instructed during 
the consent process to promptly tell the study doctor about any illness or injury.
The hospital [university, researchers] will not pay for medical care required because of a bad outcome 
resulting from participation in this research study.
The coverage for such injury or illness is only available if the Northwestern University principal 
investigator and study sponsor, if applicable, have decided that the injury/illness is directly related to the 
study drug, device, or procedures and is not the result of a pre-existing condition or the normal 
progression of the subject’s disease, or because they have not followed the directions of the study doctor. 
If their insurance is billed, they may be required to pay deductibles and co-payments that apply. They 
should check with their insurance company about any such payments.
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20. ECONOMIC BURDEN TO PARTICIPANTS
There will be no cost to subjects due to their participation in this study.
21. CONSENT PROCESS
Informed consent is a process that is initiated prior to the individual agreeing to participate in the study 
and continues throughout study participation. Extensive discussion of risks and possible benefits of study 
participation will be provided to participants and their families, if applicable. A consent form describing in 
detail the study procedures and risks will be given to the subject.
Consent forms will be IRB-approved, and the participant is required to read and review the document or 
have the document read to him or her. The investigator or designee will explain the research study to the 
participant and answer any questions that may arise. The participant will sign the informed consent 
document prior to any study-related assessments or procedures. Participants will be given the opportunity 
to discuss the study with their surrogates or think about it prior to agreeing to participate. They may 
withdraw consent at any time throughout the course of the study. A copy of the signed informed consent 
document will be given to participants for their records. The rights and welfare of the participants will be 
protected by emphasizing to them that the quality of their clinical care will not be adversely affected if 
they decline to participate in this study.
The consent process will be documented in the participant folder.
22. PROTECTED HEALTH INFORMATION (PHI AND HIPAA)
We are committed to respect participant privacy and to keep personal information confidential. When 
choosing to take part in this study, participants are giving us the permission to use their PHI that includes 
health information in their medical records and information that can identify them. For example, PHI may 
include name, address, phone number or social security number. Health information that we may collect 
and use for this research includes:
●
All information in a medical record
●
Results of physical examinations
●
Medical history including back pain history and family history of back pain
●
Lab tests, or certain health information indicating or relating to a particular condition as well 
as information collected by cellphone apps and PROs
●
Records about study medication or drugs
●
Records about MRI scans
●
Substance abuse information: current recreational drug use or history of alcohol or drug abuse
The following groups of people may give the researchers information about research participants: 
All current and previous health care providers, including but not limited to the NMFF, NMPG,
NMH. Once we have the health information listed above, we may share some of this information 
with the following people. Please note that any research information shared with people outside of 
NU and its clinical partners (or affiliates) will not contain subject’s name, address, telephone or 
social security number or any other direct personal identifier unless disclosure of the direct 
identifier is required by law [except that such information may be viewed by the Study sponsor and 
its partners or contractors at the PI’s office]
●
Authorized members of the NU workforce, who may need to see information, such as 
administrative staff members from the Office for Research, Office for Research Integrity 
and members of the Institutional Review Board (a committee which is responsible for the 
ethical oversight of the study),
●
Clinical affiliates, including but not limited the NMFF, NMH, and NMPG. Individuals’ 
participation in this clinical trial will be tracked in an electronic database and may be seen by 
investigators running other trials and by other healthcare providers having access to this 
database.
●
Other University research centers and University contractors who are also working on the study,
●
Study monitors and auditors who make sure that the study is being done properly,
●
Government agencies and public health authorities, such as the FDA and the DHHS.
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The informed consent document will include a HIPAA authorization as well.
The results of this study may also be used for teaching, publications, or presentation at 
scientific meetings. However, the individual’s name and personal information will not be used.
23. NON-ENGLISH SPEAKING PARTICIPANTS
Subjects who are unable to read, and understand English will not be enrolled into this trial.
24. QUALIFICATIONS TO CONDUCT RESEARCH AND RESOURCES AVAILABLE
This protocol requires identifying and recruiting approximately 185 individuals with chronic localized pain 
over an approximately 4 year period, with 160 of these individuals receiving opioid treatment (half with 
and half without OUD). We have had many years of experience dealing with the pain population, including 
both individuals being treated with non-opioid medications as well as those using opioids. As noted in the 
proposal, we have completed large, longitudinal studies in people with CBP and have screened over 500 
individuals with CBP over the past 3 years and entered over 200 in various previous studies. Our staff is 
experienced in out-reach and screening, and we work closely with the NUCATS Institute which provides 
assistance in recruitment. Dr. Schnitzer has an excellent working relationship with the pain physicians 
both at Northwestern Medicine and at SRAL, being on the medical staff of both institutions. Both 
institutions have large pain clinics and medical management of CBP is an integral part of specialized 
programs at each of these medical centers. The pain specialists at each institution have been supportive 
and enthusiastic in support of all previous CBP studies and their assistance has been important for our 
success. In addition, both institutions have large electronic data warehouses which we have used to help 
facilitate identification of patients with specific diagnoses and concomitant treatment. Use of these 
resources, again in conjunction with the pain physicians, has been particularly helpful in recruitment. 
Identifying, screening and enrolling 20- 25 individuals with CBP treated with opioids (half with and half 
without OUD) at each institution per year will be readily accomplished. Additionally, recruitment will be 
facilitated by the relatively short duration of this study: 4 weeks for individuals completing only Aim 1 and 
an additional ~8weeks for individuals continuing on to Aim 2, and the proximity of the imaging and 
research centers to the clinics themselves.
In preparation for this proposal we have collected actual patient volumes and descriptors for the two 
major sources of participants. Dr. Calisoff’s clinic sees around 100 patients on opioid meds per week, 
50% of these are new cases, and 50% have CBP as their main chronic pain complaint. Dr. Rodes sees 
30 patients per week on opioid meds, while the NU Pain Clinic overall sees 300 patients per week on 
opioid meds; again 50% of these suffer from CBP. Overall, both clinics estimate 50% of these patients to 
be female; 60% Caucasian and 20% Asian. We also have queried the NU EDW regarding patients seen 
with chronic pain and opioid med use over a 5-year period, using criteria for chronic pain and opioid drugs 
(ICD 9 = 338.2 AND medications: fentanyl, codeine, hydrocodone, hydromorphone, morphine, 
oxycodone, oxymorphone, and tapendatol). The search identifies 5,512 patients; 3359 female and 2153 
male; 2341 white and 1278 African American; with mean age of 50-60 years. In addition, to pilot Aim 2 
procedures, we asked both NU and AbilityLab clinics for potential CBP+O patients. Within 2 weeks 30 
candidates were identified, 6 of whom were willing to participate, and 2 actually performed parts of aim 2 
procedures. Overall, we have a large population of patients ready to be recruited into the study.
Given our previous experience conducting several successful longitudinal and cross-sectional imaging 
studies in large samples of subacute and chronic back pain patients, as well as healthy controls, the 
recruitment goals outlined above are both feasible and readily achievable. Recruitment will begin 
immediately after all the regulatory, administrative and organizational matters have been completed (first 
quarter to second quarter of year 1) and is anticipated to continue through the middle of year 4 
(approximately 4 years for enrollment). All participants will have concluded study visits by shortly after 
the middle of year 4.
Informed consent will be obtained by the project manager or research coordinator. Participants who have 
been screened previously by their physician will be referred to the study and seen in the research clinic. 
The research coordinator will discuss the study aims and objectives, the procedures that will need to be 
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followed, and the risks and potential benefits. A printed consent form will be provided to each subject 
prior to any procedures being carried out; this will be read by the potential subject and any and all 
questions answered by the coordinator and/or site investigator. A copy of the signed and witnessed 
consent will be given to the subject and the original will be placed in the subject’s study record (both 
forms will be dated and time-stamped).
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