Evaluating Specific and Non-Specific Mechanisms in Two Distinct Complementary/Integrative Interventions for Chronic Pain
Phase: EARLY_PHASE1
Conditions: Chronic Low-back Pain
Sponsor: Rush University Medical Center

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Clinical Intervention Study 
Protocol Template 

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FULL PROTOCOL TITLE 
Evaluating Specific and Non-Specific Mechanisms in Two Distinct Complementary/Integrative 
Interventions for Chronic Pain 
 
Study Chairman or Principal Investigator: 
John W Burns, PhD, Professor, Rush University Medical Center 
Stephen Bruehl, PhD, Professor, Vanderbilt University Medical Center 
Supported by: 
The National Center for Complementary and Integrative Health 
R01 AT009680-01A1 
Study Intervention Provided by: 
NA 
Sponsor of IND (IDE): 
NA 

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Tool Revision History 
Version Number: 2 
Version Date: 10/8/18 
Summary of Revisions Made: Changes made to address NCCIH staff comments/questions 
Version Number: 3 
Version Date: 5/9/19 
Summary of Revisions Made: Changes made to address recommendations from initiation site visit 
Version Number: 4 
Version Date: 6/13/19 
Summary of Revisions Made: Clarification was added surrounded the reporting of protocol deviations 
and the discontinuation of participants and the study as a whole 
Version Number: 5 
Version Date: 10/31/2019 
Summary of Revisions Made: Formatting changes, change in participant compensation rate, minor 
changes in surveys/assessments and exclusion criteria, and staff change 
Version Number: 6 
Version Date: 12/3/2019 
Summary of Revisions Made: Corrected page numbers in the Table of Contents, added bone 
demineralization, osteoporosis, and suicidal ideation to the exclusion criteria, corrected errors related to 
laboratory and therapy session procedures, formatting changes, and added the names of RUMC’s physical 
therapists 
Version Number: 7 
Version Date: 2/28/20 
Summary of Revisions Made: Added opioid-dependency to the exclusion criteria, clarified that 
participants who experience withdrawal symptoms from the initial naloxone administration will be 
excluded, and edited staff information. In the assessment of spinal stiffness section added that the 
VerteTrack device has not been approved by the FDA at the request of the VUMC IRB. 
Version Number: 8 
Version Date: 07/16/2020 
Summary of Revisions Made: Edited VUMC therapist information, added RUMC research nurse and 
additional pharmacy staff, added exclusion criteria relevant to the VerteTrack device, and added COVID- 
19 related safety precautions. 
Version Number: 9 
Version Date: 08/07/2020 
Summary of Revisions Made: Added exclusion criteria relevant to the VerteTrack device and added 
RUMC research staff. 
 
Version Number: 10 
Version Date: 09/15/2020 
Summary of Revisions Made: Edited therapy session times from 1 hour to 1-1.5 hours, removed MT 
weekly process checks from MT therapy sessions, removed spinal stiffness measurements from 3 and 6 
month follow up visits, minor grammar edits, and edited our phone screen’s exclusion criteria to be 
consistent with previous exclusion criteria. 

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Version 
Number: 
11 
Version Date: 10/12/2020 
Summary of Revisions Made: Added a BMI of ≥40 or a waist measurement of 8.5-9.5 inches or 
greater from abdomen to back to the exclusion criteria to ensure that all enrolled participants will 
fit the Vertetrack device. 
 
Version Number: 12 
Version Date: 12/11/2020 
Summary of Revisions Made: Staff change at both sites, corrected errors/typos and minor 
punctuation edits, added an online option for participants to complete their weekly post- 
treatment surveys and follow-up surveys, and added COVID-19 related safety precautions for 
MT sessions. 
 
Version Number: 13 
Version Date: 12/31/2020 
Summary of Revisions Made: We added in the contact information for the new physical 
therapists at RUMC. 
 
Version Number: 14 
Version Date: 3/17/21Summary of Revisions Made: VUMC/RUMC staff change, changes to 
exclusion criteria, clarified drug dosing information, clarified procedures for urine opioid and 
pregnancy screening tests. 
 
Version Number: 15 
Version Date: 9/2/2021 
Summary of Revisions Made: Staff changes at RUMC. 
 
Version Number: 16 
Version Date: 2/8/2022 
Summary of Revisions Made: Staff changes at VUMC, dropped mid-treatment lab visits. 
Version Number: 17 
Version Date: 8/5/2022 
Summary of Revisions Made: Staff changes at RUMC/VUMC, updated exclusion criteria, 
revised training requirements for MT therapists. 
 
Version Number: 18 
Version Date: 3/30/2023 
Summary of Revisions Made: Staff changes at VUMC 

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Version Number: 19 
Version Date: 4/24/2024 
Summary of Revisions Made: Staff changes at RUMC 
 
Version Number: 20 
Version Date: 6/12/2024 
Summary of Revisions Made: Error in the grant name label and addition of data analyst to RUMC 
 
TABLE OF CONTENTS 
Page 
Clinical Intervention Study Protocol Template...........................................................................1 
FULL PROTOCOL TITLE ......................................................................................................... 2 
Tool Revision History ................................................................................................................. 3 
TABLE OF CONTENTS .............................................................................................................. 5 
STUDY TEAM ROSTER ............................................................................................................8 
PARTICIPATING STUDY SITES ............................................................................................. 9 
PRÉCIS ..................................................................................................................................... 13 
1. STUDY OBJECTIVES ........................................................................................................... 15 
1.1 
Primary Objective ......................................................................................................... 15 
1.2 
Secondary Objectives .................................................................................................... 16 
2. BACKGROUND AND RATIONALE ................................................................................... 16 
2.1 
Background on Condition, Disease, or Other Primary Study Focus ............................. 16 
2.2 
Study Rationale ............................................................................................................. 17 
3. STUDY DESIGN ..................................................................................................................... 19 
4. SELECTION AND ENROLLMENT OF PARTICIPANTS ............................................... 20 
4.1 
Inclusion Criteria ........................................................................................................... 21 
4.2 
Exclusion Criteria .......................................................................................................... 21 
4.3 
Study Enrollment Procedures ........................................................................................ 22 
5. STUDY INTERVENTIONS ................................................................................................... 23 
5.1 
Interventions, Administration, and Duration ................................................................. 23 
5.2 
Handling of Study Interventions ................................................................................... 25 
5.3 
Concomitant Interventions .............................................................................................26 

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5.3.1 Allowed Interventions ............................................................................................... 26 
5.3.2 Required Interventions .............................................................................................. 26 
5.3.3 Prohibited Interventions ............................................................................................ 26 
5.4 
Adherence Assessment ...................................................................................................26 
6. STUDY PROCEDURES ......................................................................................................... 26 
6.1 
Schedule of Evaluations ................................................................................................ 26 
6.2 
Description of Evaluations ............................................................................................ 29 
6.2.1 Screening Evaluation ................................................................................................. 29 
6.2.2 Enrollment, Baseline, and/or Randomization ............................................................ 29 
6.2.3 Blinding ..................................................................................................................... 34 
6.2.4 Followup Visits ......................................................................................................... 35 
6.2.5 Completion/Final Evaluation .....................................................................................36 
7. SAFETY ASSESSMENTS....................................................................................................... 37 
7.1 
Specification of Safety Parameters ............................................................................... 37 
7.2 
Methods and Timing for Assessing, Recording, and Analyzing Safety Parameters ..... 38 
7.3 
Adverse Events and Serious Adverse Events ................................................................ 38 
7.4 
Reporting Procedures .................................................................................................... 39 
7.5 
Followup for Adverse Events........................................................................................ 39 
7.6 
Safety Monitoring ......................................................................................................... 40 
8. INTERVENTION DISCONTINUATION ............................................................................ 40 
9. STATISTICAL CONSIDERATIONS ................................................................................... 41 
9.1 
General Design Issues ................................................................................................... 41 
9.2 
Sample Size and Randomization ................................................................................... 42 
Treatment Assignment Procedures .........................................................................................44 
9.3 
Definition of Populations .............................................................................................. 45 
9.4 
Interim Analyses and Stopping Rules ........................................................................... 46 
9.5 
Outcomes ....................................................................................................................... 46 
9.5.1 Primary Outcome ...................................................................................................... 47 
9.5.2 Secondary Outcomes ................................................................................................. 47 
9.6 
Data Analyses ................................................................................................................ 47 
10. DATA COLLECTION AND QUALITY ASSURANCE ................................................... 52 
10.1 
Data Collection Forms .................................................................................................. 52 
10.2 
Data Management ..........................................................................................................53 
10.3 
Quality Assurance ..........................................................................................................54 

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10.3.1 Training ..................................................................................................................... 54 
10.3.2 Quality Control Committee ....................................................................................... 54 
10.3.3 Metrics....................................................................................................................... 54 
10.3.4 Protocol Deviations ................................................................................................... 54 
10.3.5 Monitoring ................................................................................................................. 54 
11. PARTICIPANT RIGHTS AND CONFIDENTIALITY .................................................... 55 
11.1 
Institutional Review Board (IRB) Review .................................................................... 55 
11.2 
Informed Consent Forms ................................................................................................55 
11.3 
Participant Confidentiality..............................................................................................55 
11.4 
Study Discontinuation ....................................................................................................56 
12. COMMITTEES ..................................................................................................................... 56 
13. PUBLICATION OF RESEARCH FINDINGS .................................................................. 56 
14. REFERENCES ...................................................................................................................... 56 
15. SUPPLEMENTS/APPENDICES ......................................................................................... 66 
I. Procedures Schedule 
II. Informed Consent Form Template 
III. Other (add as many appendices as necessary) 

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STUDY TEAM ROSTER 
Principal Investigators: 
 
John W. Burns, PhD 
Department of Behavioral Sciences 
Rush University Medical Center 
1645 West Jackson Blvd, Suite 400 
Chicago IL 60612 
Ph. 312-942-0379 
Fax: 312-942-4990 
Email: John_Burns@rush.edu 
 
Stephen Bruehl, Ph.D. 
Professor 
Department of Anesthesiology 
Vanderbilt University Medical Center 
701 Medical Arts Building 
211 21st Avenue South 
Nashville, TN 37212 
Phone: (615) 936-1821 
Email: stephen.bruehl@vumc.org 
 
Co-Investigators: 
 
Joel Bialosky, PhD 
Clinical Assistant Professor 
University of Florida 
PO Box 100154 
Gainesville, FL, 32601 
Phone: 352 273 8636 
E-Mail: bialosky@phhp.ufl.edu 
 
Greg Kawchuk, PhD 
University of Alberta 
2-55 Corbett Hall 
8205 114 St NW City 
Alberta, 
Canada 
Phone: 780 492 6891 
E-Mail: greg.kawchuk@ualberta.ca 
 
Asokumar Buvanendran, MD 
Professor 
Department of Anesthesiology 
Rush University Medical Center 
1645 W Jackson Blvd 
Chicago, IL 60612 
Phone: 312 942 3685 
E-Mail: asokumar@aol.com 

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James Carmody, PhD 
Professor 
Univ of Massachusetts Medical School 
55 Lake Ave North 
Worcester, MA 01655 
Phone: 508 856 1205 
E-Mail: james.carmody@umassmed.edu 
 
Dan Larach, MD, MSTR, MA 
Assistant Professor of Anesthesiology 
Division of Pain Medicine 
Vanderbilt University Medical Center 
Medical Arts Building 
1211 21st Ave S Ste 708 
Nashville, TN 37212-2717 
Phone: (615) 875-8795 
Email: daniel.larach@vumc.org 
 
 
 
PARTICIPATING STUDY SITES 
John W. Burns, PhD 
Center for Pain Studies 
Department of Behavioral Sciences 
Rush University Medical Center 
1645 West Jackson Blvd, Suite 400 
Chicago IL 60612 
Ph. 312-942-0379 
Fax: 312-942-4990 
Email: John_Burns@rush.edu 
 
Stephen Bruehl, Ph.D. 
Professor 
Department of Anesthesiology 
Vanderbilt University Medical Center 
701 Medical Arts Building 
211 21st Avenue South 
Nashville, TN 37212 
Phone: (615) 936-1821 
Email: stephen.bruehl@vumc.org 

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Joel Bialosky, PhD 
Clinical Assistant Professor 
University of Florida 
PO Box 100154 
Gainesville, FL, 32601 
Phone: 352 273 8636 
E-Mail: bialosky@phhp.ufl.edu 
 
James Carmody, PhD 
Professor 
Univ of Massachusetts Medical School 
55 Lake Ave North 
Worcester, MA 01655 
Phone: 508 856 1205 
E-Mail: james.carmody@umassmed.edu 
 
Study Staff 
Melissa Chont 
Clinical/Translational Research Coordinator III 
Department of Anesthesiology 
Vanderbilt University 
324 Medical Arts Building 
1211 21st Avenue South 
Nashville, TN 37212 
Office: (615) 936-5664 
Email: melissa.chont@vumc.org 
 
Nicole Heath, PhD 
Licensed Clinical Psychologist 
Assistant Professor 
Department of Psychiatry and Behavioral Sciences 
Rush University Medical Center 
1645 W. Jackson, Suite 400 
Chicago, IL 60612-2344 
Phone: (312) 942-0763 
Email: Nicole_heath@rush.edu 
 
 
Laurie Gold Carroll, PT, DPT 
Department of Physical Therapy 
1725 W Harrison St., Suite 440 
Chicago, IL 60612 
Phone: (312) 942-5847 
Email: laurie_carroll@rush.edu 
 
Rogelio A. Coronado, PT, PhD 
Research Assistant Professor 
Department of Orthopedic Surgery 
Vanderbilt University Medical Center 
1215 21st Avenue South, MCE-South, Suite 4200 

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Nashville, TN 37232 
Phone: (615) 936-4348 
Email: rogelio.coronado@vumc.org 
 
Carrie E. Brintz, PhD 
Assistant Professor of Anesthesiology 
Division of Pain Medicine 
Osher Center for Integrative Medicine 
Vanderbilt University Medical Center 
3401 West End Ave., Suite 380 
Nashville TN 37203 
Phone: (615) 322-6033 
Email: carrie.brintz@vumc.org 
 
Mandi Mizner, MSN, MSSW, APRN, LMSW 
Nurse Practitioner 
Osher Center for Integrative Medicine at Vanderbilt 
3401 West End Ave., Suite 380 
Nashville TN 37203 
Phone: 615-343-1554 
Email: mandi.mizner@vumc.org 
 
Dana Mikrut, PharmD, BCPS 
Investigational Drug Service 
Department of Pharmacy 
Rush University Medical Center 
1653 W Congress Pkwy 
Chicago IL, 60612 
Phone: (312) 942-3018 
Email: dana_mikrut@rush.edu 
 
My G Ly, PharmD, BCOP 
Investigational Drug Service 
Department of Pharmacy 
Rush University Medical Center 
1653 W Congress Pkwy 
Chicago IL, 60612 
Phone: (312) 563-1246 
Email: my_g_ly@rush.edu 
 
Stacey Kuboske, PharmD MS 
Clinical Pharmacist, Investigational Drug Service (IDS) 
Vanderbilt University Hospital Pharmacy 
1211 Medical Center Drive, VUH Room B-127 
Nashville, TN 37232-7610 
Phone: 615-343-1641 
Email : stacey.l.kuboske@vumc.org 
 
Wendy Kreider, RN, BSN, MS 
Clinical Research Nurse III 
Department of Anesthesiology 

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Rush University Medical Center 
1750 W Harrison St. 
Chicago, IL 60612 
Phone: 312-942-1982 
Email: Wendy_Kreider@rush.edu 
 
 
Latrice Yates 
Epi Research Assistant 
Department of Psychiatry and Behavioral Sciences 
1645 West Jackson Blvd, Suite 400 
Chicago, IL 60612 
Rush University Medical Center 
Phone: 312-942-5932 
Email: Latrice_Yates@rush.edu 
 
Elias Mihan 
Research Assistant I 
Department of Anesthesiology 
Vanderbilt University Medical Center 
324 Medical Arts Building 
1211 21st Avenue South 
Nashville, TN 37212 
Phone: 615-875-6530 
Email: elias.mihan@vumc.org 
 
 
Taylor Sorrells PT, DPT 
Department of Physical Therapy 
1725 W Harrison St., Suite 440 
Chicago, IL 60612 
Phone: (312) 942-5847 
Email : Taylor_Sorrells@rush.edu 
 
 
Sumihiro Suzuki, PhD 
Data Analyst/Statistician 
Department of Family and Preventative Medicine 
Rush University Medical Center 
1700 W VanBuren St., Suite 470 
Chicago, IL 60612 
Phone: (312)563-3718 
 
 
 
 
 
 

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The PIs (Bruehl & Burns) should be notified regarding protocol requirement questions, 
adverse events, unblinding a participant, questions surrounding eligibility or any other 
study logistical question. Dr. Buvanendran and Dr. Larach will be notified regarding 
medical questions. The Investigation Pharmacy will be contacted for all questions related 
to medication and lab drug condition. Co-Investigators Drs. Carmody and Bialosky will 
be unblinded to participant intervention and will be consulted about any questions related 
to intervention adherence or delivery. Requests for additional supplies will be made to the 
study coordinators and approved by the PIs. 
PRÉCIS 
Study Title 

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Evaluating Specific and Non-Specific Mechanisms in Two Distinct 
Complementary/Integrative Interventions for Chronic Pain 
Objectives 
Aim 1: Test effects of 2 treatments on non-specific mechanisms. We will test to what degree 
Mindfulness Therapy (MT) and Spinal Manipulation Therapy (SMT) produce changes in the 
3 categories of non-specific mechanisms. We hypothesize that MT and SMT will produce 
changes in these non-specific mechanisms to approximately the same degree. 
Aim 2: Test effects of 2 treatments on specific mechanisms. We will test to what degree MT 
and SMT produce changes in treatment-specific mechanisms (MT: changes in how patients 
think about pain; SMT: spinal stiffness). We expect that MT and SMT will each affect their 
own treatment-specific mechanism more than will the other treatment (e.g., MT will produce 
larger changes in mindfulness than SMT; SMT will produce larger changes in spinal stiffness 
than MT). 
Aim 3: Test relative predictive validity of non-specific and specific mechanisms. We will test 
to what degree changes in non-specific and specific mechanisms predict changes in pain, 
mood and function, and whether these relationships depend on the treatment received. We 
will first test Mechanism Change x Treatment interactions to determine whether changes in 
any candidate mechanisms predict outcomes to a greater degree in one treatment than the 
other. In the absence of interactions, we will test the degree to which changes in non-specific 
and specific mechanisms account for unique and shared variance in predicting outcomes. 
Aim 4: To address competing causation paths, we will test lagged and cross-lagged effects of 
early-treatment changes in non-specific and specific mechanisms predicting late-treatment 
changes in outcomes. 
Design and Outcomes 
In the proposed study, individuals with chronic low back pain (CLBP; n=286) will be 
assigned randomly to MT or SMT. For both MT and SMT, treatment will consist of 8 
weekly, 60-90 min individual sessions. Self-report mechanism and outcome variables will be 
assessed at baseline, 1-day after each weekly session (via phone by research staff blind to 
condition or online by the patient), and at 3- and 6-mo follow-up. Spinal stiffness will be 
assessed for both conditions prior to and after each session. Endogenous opioid (EO) function 
and conditioned pain modulation (CPM) will be assessed for both conditions at each 
laboratory session. Specific mechanism factors were chosen to match the theoretical bases of 
each treatment. Mindfulness will be the specific mechanism for MT because (a) it is a key 
psychological factor targeted by MT and (b) preliminary research points to mindfulness as a 
viable mediator of psychological treatments. Spinal stiffness will be the specific mechanism 
for SMT because (a) it is a mechanical marker that can be measured and (b) changes in spinal 
stiffness have been shown to mediate treatment effects. Non-specific mechanisms will 
include changes in (a) CPM assessed via quantitative sensory testing (QST) methods; (b) EO 
function; (c) pain self-efficacy and catastrophizing; (d) patient expectations of benefit and 
quality of the therapeutic relationship. We will assess outcomes following published Initiative 
on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) 
recommendations. Pain interference (i.e., reported degree of interference in daily activities 
that is attributed to chronic pain) will be the primary outcome as it is equally relevant to both 
treatments, and given findings that reduction in pain intensity is not a primary focus of MT. 
Secondary outcomes will be pain intensity, mood, pain medication use, and use of pain- 
related healthcare. 

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Interventions and Duration 
Mindfulness Training (MT) 
Patients will receive training in mindfulness through (a) body scan meditation, a gradual 
moving of attention through the body, accompanied by awareness of breathing and other 
bodily sensations while in a lying position, (b) sitting meditation, focusing on awareness of 
breathing, bodily sensations, thoughts, and emotions, practiced sitting on a chair or cushion, 
(c) gentle movement exercises intended to develop awareness (mindfulness) during 
movement. Each session includes practice of these mindfulness techniques. In-session 
didactic material, interactions and discussion on subjects’ experiences of developing and 
applying mindfulness in everyday life are also part of each session. In-session activities 
include suggestions for application of mindfulness as a method for responding positively to 
stress; dealing with the challenges of pain; and exercises focusing on the challenges and 
achievements patients experience in integrating mindfulness into their lives and the stressful 
situations they encounter. Additional discussion will focus on stress reactivity. To help 
patients deal with obstacles to increasing mindfulness, they will be taught problem-solving 
skills to develop solutions to meet MT goals. Finally, patients will develop a written 
maintenance plan that includes a list of short- and long-term goals for applying mindfulness 
methods and a plan for dealing with possible setbacks. 
 
Spinal Manipulation Therapy (SMT) 
SMT sessions will reflect a similar visit pattern and duration as MT sessions. Recent work 
showed small differences lacking clinical meaningfulness when comparing SMT provided 1, 
2, or 3 times per week.(116) Furthermore, our visit pattern is consistent with professional 
guidelines. We will administer 2 SMT techniques each session, both of which have 
demonstrated effectiveness and are common for conservative management of individuals 
with CLBP. We will use scripted interactions between the physical therapist (PT) providing 
the SMT and subjects to stimulate therapist/subject relationships more consistent with the 
relationships that will develop in MT. Each SMT session will be organized as follows: 1) 
Participants will lie on the SMT table for 20 mins, while the PT sits approximately 6 ft away. 
As part of the script, the PT will review with subjects the inclusion/exclusion criteria 
ostensibly to ensure that nothing has changed. 2) The PT will perform the 2 SMT techniques 
during the next 20 mins. 3) Subjects will lie on the SMT table for the remaining 20 mins, 
while the PT sits approximately 6 feet away. As part of the script, the PT will ask subjects to 
perform a posterior pelvic tilt exercise. Subjects attempting to enter into discussion of issues 
beyond the scripted plan will be told, ‘‘I’m sorry but because this is a research study I am not 
allowed to discuss this with you.” 
Each individual participant will be on study for 38 weeks. This includes baseline assessments, 
pre-treatment assessments, 8 therapy sessions, post-treatment assessments, and 3- and 6- 
month follow-up assessments. 
Sample Size and Population 
Participants will be 286 individuals experiencing CLBP recruited through referrals 
from staff at the University Pain Center, Midwest Orthopedic Clinic and 
Neurosurgery Clinic at Rush University, and at the Vanderbilt University Medical 
Center Interventional Pain Clinic. Flyers posted in community physician waiting 
rooms, local newspaper ads, and online patient recruitment systems will also be used. 
Based on our experience with randomized controlled trials (RCTs) involving CLBP 

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patients, we expect 16% drop out, and therefore plan to enroll 286 people to increase 
chances of 240 subjects completing follow-up. 
 
Inclusion criteria are: 1) significant daily chronic pain intensity (≥4 on a 10-point 
scale) and interference in performing daily activities due to pain (≥3 on a 10-point 
scale) for at least 3 months; 2) age 18-75 years, and 3) not using opioid analgesics or 
Kratom on a daily basis or within 3 days of each laboratory session (confirmed via 
urine drug screen). 
 
Exclusion criteria are: 1) meet criteria for past or present psychotic or bipolar disorders; 2) 
inability to understand English well enough to complete questionnaires or participate in therapy; 
3) pain due to malignant conditions, rheumatoid arthritis, frequent migraines or tension 
headaches, complex regional pain syndrome, or fibromyalgia syndrome; 4) lumbar surgery 
within past 6 months; 5) pregnant; 6) signs of nerve root compression (ie, positive straight-leg 
raise <45○); 7) liver disease such as hepatitis or cirrhosis; 8)osteoporosis; 9) active suicidal 
ideation with intent; 10) opioid-dependency or daily use of Kratom; 11) inability to hold breath 
for 15 seconds; 12) acute trauma to spine; 13) long term use of corticosteroids; 14) have a spinal 
cord stimulator, an IT pump, or a similar device; 15) history of spinal fusion surgery; 16) 
arthritis of the hand, carpal tunnel syndrome, or any neuropathic pain diagnoses affecting the 
upper limbs; or 17) a BMI of ≥40. 
 
 
1. STUDY OBJECTIVES 
1.1 
Primary Objective 
The primary objective is to examine the degree to which MT and SMT exert effects 
on the non-specific mechanism, EO function. We will test to what degree MT and 
SMT produce pre- to mid- to post-treatment changes in EO function. Hypothesis 1: 
MT and SMT will produce near equivalent effects on EO function. 
1.2 
Secondary Objectives 
A secondary objective is to examine the degree to which MT and SMT exert effects 
on the other non-specific mechanisms: CPM, pain-related cognitions, the working 
alliance and patient expectations. Hypothesis 2: MT and SMT will produce near 
equivalent effects on these non-specific mechanisms. 
 
Another secondary objective is to test the effects of MT and SMT on specific 
mechanisms. We will test to what degree MT and SMT produce changes in treatment- 
specific mechanisms (MT: changes in how patients think about pain; SMT: spinal 
stiffness). Hypothesis 2: MT and SMT will each affect their own treatment-specific 
mechanism more than will the other treatment (e.g., MT will produce larger changes 
in mindfulness than SMT; SMT will produce larger changes in spinal stiffness than 
MT). 
 
A third secondary objective is to test the relative predictive validity of non-specific 
and specific mechanisms. We will test to what degree changes in non-specific and 

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specific mechanisms predict changes in pain, mood and function, and whether these 
relationships depend on the treatment received. We will first test Mechanism Change 
x Treatment interactions to determine whether changes in any candidate mechanisms 
predict outcomes to a greater degree in one treatment than the other. In the absence of 
interactions, we will test the degree to which changes in non-specific and specific 
mechanisms account for unique and shared variance in predicting outcomes. 
 
A final secondary objective is to examine competing causation paths. We will test 
lagged effects of early-treatment changes in specific and non-specific mechanisms on 
predicting late-treatment changes in outcomes, and vice versa. 
 
 
2. BACKGROUND AND RATIONALE 
2.1 
Background on Condition, Disease, or Other Primary Study Focus 
Chronic pain affects as many as 100 million individuals in the US alone (1), with 
management of chronic pain in recent years increasingly employing long-term opioid 
analgesic therapy (2-5). Such treatments carry the risk of serious side effects, misuse 
and addiction. In parallel, Complementary/Integrative (C/I) chronic pain interventions 
have also proliferated in recent years (e.g., Mindfulness Training [MT], spinal 
manipulation therapy [SMT]). Many of these approaches have support for efficacy, 
and pose low risk of side effects (6). The hope that interventions other than 
pharmacological ones can reduce pain and increase function has been partly realized. 
Thus, the popularity of C/I treatments for chronic pain has grown (7). 
Most research regarding C/I interventions has focused on questions regarding overall 
treatment efficacy. That is, questions regarding “Does it work to improve pain and 
function?” have been in the forefront. Although establishing efficacy is vital, the bias 
in RCT research toward investigating only efficacy has left equally important 
questions about treatment mechanisms unanswered. Little attention has been devoted 
to explicitly testing how C/I pain treatments work, let alone whether they do so 
because of mechanisms specified by theory. Questions regarding “How does it work 
to improve pain and function?” have been relatively neglected. 
2.2 
Study Rationale 
On one level are questions about mechanisms specified by theory (“specific 
mechanisms”). C/I treatments are each based on distinct theories of behavior, 
cognition, emotion, physical function and physiological pathways. From these 
principles, investigators derive putative therapeutic mechanisms. For example, MT is 
based on the premise that excessive attention to the “threat” aspect of pain generates 
negative affective responses thereby increasing pain and suffering. MT may work to 
improve patient function by altering cognitive processes or how a patient thinks about 
pain. This would include decreasing attentional fixation on pain-related sensations, 
cognitions and affect states, thereby reducing reactivity and developing the facility to 
redirect attention to sensations that do not cause emotional arousal. A tendency in 
evaluating MT outcomes research is to assume that if pre- to post-treatment gains are 

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observed, then changes in mindfulness are the primary agents bringing about those 
improvements. This remains an assumption that has not yet been subjected to 
rigorous empirical tests. In short, because many RCTs have not evaluated whether 
theoretically-specified mechanisms are valid, we do not yet know whether or to what 
degree the thought, emotion and behavior patterns we encourage patients to change 
are the actual vehicles by which they improve. 
On a second level are questions about therapeutic mechanisms that are not 
specifically linked to any particular treatment approach in affecting outcomes, but 
have well-documented effects. These variables may be shared across C/I 
interventions, and may be responsible to some extent for their efficacy. These “non- 
specific mechanisms” include factors falling into at least 3 categories: changes in 
endogenous pain inhibitory systems (e.g., endogenous opioid [EO] function; 
conditioned pain modulation), changes in pain-related cognition (e.g., pain 
catastrophizing; self-efficacy), and therapy factors (therapeutic relationship, patient 
expectations). Non-specific mechanism factors have rarely been studied directly in 
RCTs of C/I interventions. However, the contribution of these mechanisms has been 
studied indirectly in research comparing active C/I interventions to sham control 
treatments (e.g., acupuncture vs sham acupuncture). Results have tended to reveal 
similar improvements on primary outcomes (i.e., pain, mood, function) between 
active and sham treatments (8,9). Findings where the target intervention allegedly 
driven by a specific mechanism produces similar effects to a sham intervention free 
of the specific mechanism suggests that mechanisms shared across the target and 
sham procedures were at work. Without explicit tests of the effects of these non- 
specific, shared mechanisms, it is not clear to what extent effects attributed to 
putative specific mechanisms may simply be proxies for the effects of non-specific 
mechanisms. Therefore, we do not yet have firm empirical bases for determining 
whether C/I pain treatments work for the reasons specified by theory, through non- 
specific shared mechanisms, or through some combination of these factors. 
Addressing this knowledge gap is critical to the science and practice of C/I pain 
interventions because it: 1) tests theory validity, 2) provides an empirically-supported 
rationale for asking people with pain to devote time, energy and resources to common 
C/I techniques, 3) identifies the effective mechanisms of these pain treatments and 
reveals those that may be redundant or inert, 4) would highlight what exactly must be 
preserved in C/I pain treatments as they move from well-controlled RCTs to real- 
world clinical practice settings (92), and 5) provides theoretical and empirical 
principles by which to enhance the C/I techniques that are most closely linked to the 
largest benefits and potentially combine C/I interventions having complementary 
mechanistic effects. Addressing this knowledge gap requires that we shift attention in 
C/I pain research away from evaluating only treatment efficacy toward research that 
uncovers core treatment mechanisms. 
The proposed comparative mechanism study will compare the degree to which MT 
and SMT activate both specific and non-specific mechanisms among individuals with 
chronic low back pain (CLBP), and the degree to which these mechanisms in turn 
affect key pain-related outcomes (e.g., pain interference, pain intensity). MT and 
SMT were chosen because: 1) data supports their efficacy; 2) their hypothesized 

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specific mechanisms of action are quite distinct; 3) they vary with regard to the 
degree of active vs passive participation required of patients; and 4) their use is 
widespread and growing. 
Although there is mounting evidence that C/I interventions, such as MT and SMT, 
reduce pain and improve function in individuals with CLBP, evidence supporting 
how they work to bring about favorable outcomes is incomplete. Only a handful of 
studies have directly addressed whether MT works via its theoretically specific 
mechanism, increased mindfulness, and whether SMT works via its theoretically 
specific biomechanical mechanism (decreased spinal stiffness). Given that attention 
control or sham procedures produce a large measure of the effects shown by the 
active treatments, an alternative hypothesis is that C/I interventions work largely via 
non-specific mechanisms that many treatment approaches have in common. Much 
support for this inference comes from attention control and sham procedures wherein 
the suspected nonspecific mechanisms were not directly measured. Other disparate 
studies have assessed the role of factors such as evoked pain responsiveness, EO 
function, therapeutic relationship, etc., but not in a programmatic way, nor have they 
done so in concert with testing the effects of specific mechanisms. 
Despite preliminary work in this area, definitive support for any putative mechanism 
for any C/I intervention is not yet available. We can glean only imprecise outlines 
about how C/I treatments work from a few studies, most of which were not designed 
to test mechanisms. Thus, we need comprehensive and well-powered studies that 
incorporate multiple treatments and multiple mechanism candidates to compare and 
contrast mechanism effects. If we are to advocate for the use of C/I interventions to 
treat chronic pain, we must know whether they are working at least in part via their 
specific mechanisms; putative mechanisms which in turn guide the development and 
use of specific therapeutic techniques. For example, to recommend use of SMT 
instead of an alternative, we should know that it produces improvements in pain and 
function via measurable mechanical changes wrought with spinal manipulation 
techniques. At the same time, nonspecific mechanisms are clearly at work in C/I 
interventions. Rather than characterize them as placebo or nuisance factors in our 
attempts to reveal specific mechanisms, we submit that we should instead define them 
and measure the magnitude of their effects, particularly in concert with specific 
mechanisms. For example, rather than seeing the therapeutic relationship as adding 
noise to the specific mechanism signal, we believe it may be more useful to quantify 
the precise effect of this treatment mechanism (114). If the therapeutic relationship 
accounts for 20% of a given treatment’s effects, then perhaps training therapists to be 
more interpersonally adept would become a critical mission (see Kaptchuk et al (43) 
regarding effects of an augmented therapeutic relationship). 
 
3. STUDY DESIGN 
To break new ground in the study of C/I chronic pain mechanisms, and to lay 
groundwork for a new research strategy that focuses on principles of change and 
mechanisms, we propose a comparative mechanisms study that integrates RCT 
methods with methods developed in the psychotherapy process literature to better 
address questions of mechanism. As per Kazdin (92), frequent assessments of 

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mechanisms and outcomes during treatment are needed to examine patterns of change 
from early-late treatment and to examine lagged effects. 
In the proposed study, individuals with CLBP (N=286) will be assigned randomly to 
MT or SMT. For both MT and SMT, treatment will consist of 8 weekly, 60-min 
individual sessions. Self-report mechanism and outcome variables will be assessed at 
baseline, 1-day after each weekly session (via phone by an RA blind to condition or 
online by the patient), and at 3- and 6-mo follow-up. Spinal stiffness will be assessed 
for both conditions prior to and after each therapy session. EO function and CPM will 
be assessed for both conditions at each laboratory session due to the complexity of 
this assessment. Specific mechanism factors were chosen to match the theoretical 
bases of each treatment. Mindfulness will be the specific mechanism for MT because 
(a) it is a key psychological factor targeted by MT (10) and (b) preliminary research 
points to mindfulness as a viable mediator of psychological treatments (16). Spinal 
stiffness will be the specific mechanism for SMT because (a) it is a mechanical 
marker that can be measured and (b) changes in spinal stiffness have been shown to 
mediate treatment effects (39). Non-specific mechanisms will include changes in (a) 
CPM assessed via QST methods; (b) EO function; (c) pain self-efficacy and 
catastrophizing; (d) patient expectations of benefit and quality of the therapeutic 
relationship. We will assess outcomes following IMMPACT recommendations. Pain 
interference will be the primary clinical outcome as it is equally relevant to both 
treatments, and given findings (97) that reduction in pain intensity is not a primary 
focus of MT. Secondary outcomes will be pain intensity, mood, pain medication use, 
and use of pain-related healthcare. 
Given existing RCTs,(117-123), we expect MT and SMT to produce similar overall 
outcomes. As a comparative mechanisms study, analyses will focus primarily on 
documenting and characterizing mechanism effects. Note that all mechanism and 
outcome measures will be completed by all participants in both treatments at each 
assessment point, thus allowing us to test the degree to which mechanisms not 
specific to a treatment change and account for outcomes. To support the existence of 
a specific mechanism, analyses would reveal that: 1) putative specific mechanisms 
(i.e., mindfulness in MT, spinal stiffness in SMT) will show the largest pre-post 
changes in the relevant treatment condition (e.g., MT mindfulness changes > SMT 
mindfulness changes); 2) substantial changes in the mechanism will precede and 
predict substantial subsequent changes in outcomes only in the relevant treatment 
(e.g., mindfulness changes predict pain interference changes only in MT). 
We will also take full advantage of this design and evaluate effects of mechanisms 
beyond pre- to post-treatment changes in outcomes. To our knowledge, no 
methodologically rigorous published study has yet examined effects of mechanisms 
on pre-post changes in concert with effects of mechanisms on maintenance or 
expansion of gains during follow-up. It may be that the true value of a mechanism 
may only be revealed through its effects on sustained gains out to 6-mos after 
treatment. Thus, mechanisms that do not show strong links with pre-post outcome 
changes may emerge as delayed predictors of 3- and 6-mos outcomes. Only by 
separating immediate pre-post mechanism effects from longer-term post-treatment 
mechanism effects can we build on current knowledge regarding the extended value 

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of C/I interventions for chronic pain. 
 
4. SELECTION AND ENROLLMENT OF PARTICIPANTS 
Participants will be recruited through referrals from staff at the University Pain 
Center, Midwest Orthopedic Clinic and Neurosurgery Clinic at Rush University, the 
Vanderbilt University Medical Center Interventional Pain Clinic, and the Osher 
Center for Integrative Medicine at Vanderbilt. Additionally, we will recruit in the 
community via flyers posted at community physician waiting rooms and other public 
sites, local newspaper ads, Facebook ads, and online patient recruitment systems 
(Vanderbilt e-mail recruitment system, My Research at Vanderbilt, Research Match). 
My Research at Vanderbilt is an informatics-based recruitment tool that uses 
Vanderbilt University Medical Center EMR data to match individuals expressing 
interest in research participation with studies which may be of interest to them. 
Research Match (ResearchMatch.org) is a national electronic, web-based recruitment 
tool that was created through the Clinical & Translational Science Awards 
Consortium in 2009 and is maintained at Vanderbilt University as an IRB-approved 
data repository. We have used all of these recruitment approaches in our prior work 
with a high degree of success. In addition, potentially qualifying individuals who 
have participated in past studies in our labs who have expressed an interest in writing 
to be contacted for future research may be contacted as well. 
Participants will: 1) have significant daily chronic pain intensity (≥4 on a 10-point 
scale) and interference in performing daily activities due to pain (≥3 on a 10-point 
scale) for at least 3 months; and 2) be between age 18-75 years inclusive. Participants 
will not be using opioid analgesics or Kratom on a daily basis or within 3 days of 
each laboratory session (confirmed via urine drug screen). 
 
Participants will not: 1) meet criteria for past or present psychotic or bipolar 
disorders; 2) be unable to understand English well enough to complete questionnaires 
or participate in therapy; 3) have pain due to malignant conditions, rheumatoid 
arthritis, frequent migraines or tension headaches, complex regional pain syndrome, 
or fibromyalgia syndrome; 4) have had lumbar surgery within past 6 months; 5) be 
pregnant; 6) have signs of nerve root compression (i.e., positive straight-leg raise 
<45○); 7) have liver disease such as hepatitis or cirrhosis; 8) have osteoporosis; 9) an 
active suicidal ideation with intent; 10) have opioid-dependency or daily use of 
Kratom; 11) have trouble holding their breath for 15 seconds; 12) have acute trauma 
to spine; 13) have long term use of corticosteroids; 14) have a spinal cord stimulator, 
an IT pump, or a similar device; 15) history of spinal fusion surgery; 16) arthritis of 
the hand, carpal tunnel syndrome, or any neuropathic pain diagnoses affecting the 
upper limbs; or 17) a BMI of ≥40. 
4.1 
Inclusion Criteria 
Inclusion criteria are: 1) musculoskeletal pain of the lower back and/or leg pain 
stemming from degenerative disk disease, spinal stenosis, or disk herniation 
(radiculopathy subcategory), or muscular or ligamentous strain (chronic myofascial 
pain subcategory); 2) able to verify chronic pain diagnosis via written confirmation 

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from a physician; 3) significant daily chronic pain intensity (≥4 on a 10-point scale) 
and interference in performing daily activities due to pain (≥3 on a 10-point scale) for 
at least 3 months; 4) age 18-75 years, and 5) not using opioid analgesics or Kratom on 
a daily basis or within 3 days of each laboratory session (confirmed via urine drug 
screen). 
 
Eligibility will be determined by MD review of medical records and RA 
administration of relevant items from the Mood Disorder, Psychotic Screening and 
Substance Use Disorders Modules of the Structured Clinical Interview for DSM-V 
Axis I Disorders - Non-Patient Edition (SCID-V/NP;77). General health will be 
assessed as will circumstances of the onset of low back pain, the sequence of events 
in terms of medical intervention to date, exacerbating/ameliorating factors, 
medications used currently and in the past, previous diagnostic modalities employed, 
and previous medical interventions and their impact. 
4.2 
Exclusion Criteria 
Exclusion criteria are: 1) meet criteria for past or present psychotic or bipolar 
disorders; 2) inability to understand English well enough to complete questionnaires 
or participate in therapy; 3) pain due to malignant conditions, rheumatoid arthritis, 
frequent migraines or tension headaches, complex regional pain syndrome, or 
fibromyalgia syndrome; 4) lumbar surgery within past 6 mos; 5) pregnant; 6) signs of 
nerve root compression (i.e., positive straight-leg raise <45○); 7) have liver disease 
such as hepatitis or cirrhosis; 8) have osteoporosis; 9) have an active suicidal ideation 
with intent; 10) opioid-dependency or daily use of Kratom; 11) inability to hold 
breath for 15 seconds; 12) acute trauma to spine; 13) long term use of corticosteroids; 
14) have a spinal cord stimulator, an IT pump, or a similar device; 15) history of 
spinal fusion surgery; 16) arthritis of the hand, carpal tunnel syndrome, or any 
neuropathic pain diagnoses affecting the upper limbs; or 17) a BMI of ≥40. 
 
4.3 
Study Enrollment Procedures 
Participants will be recruited through referrals from staff at the University Pain 
Center, Midwest Orthopedic Clinic and Neurosurgery Clinic at Rush University, the 
Vanderbilt University Medical Center Interventional Pain Clinic, and the Osher 
Center for Integrative Medicine at Vanderbilt. Additionally, we will recruit in the 
community via flyers posted at community physician waiting rooms and other public 
sites, local newspaper ads, Facebook ads, and online patient recruitment systems 
(Vanderbilt e-mail recruitment system, My Research at Vanderbilt, Research Match). 
My Research at Vanderbilt is an informatics-based recruitment tool that uses 
Vanderbilt University Medical Center EMR data to match individuals expressing 
interest in research participation with studies which may be of interest to them. 
Research Match (ResearchMatch.org) is a national electronic, web-based recruitment 
tool that was created through the Clinical & Translational Science Awards 
Consortium in 2009 and is maintained at Vanderbilt University as an IRB-approved 
data repository. We have used all of these recruitment approaches in our prior work 
with a high degree of success. In addition, potentially qualifying individuals who 

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have participated in past studies in our labs who have expressed an interest in writing 
to be contacted for future research may be contacted as well. 
 
Interested individuals will be able to contact the designated study research assistant 
by phone or email. Individuals expressing an interest will first be provided verbally 
with information on the study procedures, risks, and benefits, and if interested, will be 
given the opportunity to read the IRB-approved informed consent form. All questions 
from potential subjects will be answered by the study representative as accurately as 
possible. All individuals agreeing to participate will provide written informed consent 
prior to beginning any study procedures. Subject recruitment and consent procedures 
will be carried out by individuals designated and trained by each site PI and the IRB 
to carry out these procedures (i.e., the proposed research assistants). Potential subjects 
will be told that they will be compensated $605 for their time and effort to participate 
in all of the assessment and therapy sessions. In the Consent Form, it will be 
emphasized that subjects may discontinue participating at any time and still receive 
prorated compensation. The recruiter will inform potential subjects that participation 
is completely voluntary, and they may withdraw at any time without penalty or 
running the risk of jeopardizing current and future treatment at the Rush or Vanderbilt 
medical centers. 
 
Study patients (n=286) will be randomized to receive either MT or SMT. The order of 
drug administration for each laboratory session will also be separately randomized 
and counterbalanced (placebo vs. naloxone) for both of the assessment time points 
(in double-blinded fashion). All randomization will be carried out using the Proc Plan 
procedure in SAS version 9.2 (SAS Institute, Cary, NC). This SAS procedure will be 
used to generate a randomization schedule for each sequential study slot (MT vs. 
SMT and the order of naloxone/placebo administration in each set of lab visits). 
Study subjects will be assigned to these previously randomized study slots in the 
order that they are enrolled, and the previously determined randomization status 
associated with each slot will determine the intervention condition each subject is in 
and the order of drug administration for each session. This randomized order will be 
maintained even if study appointments are missed (applies only to drug order in 
laboratory sessions). In the event of a true study dropout, that slot is considered used 
and future subjects will not be assigned to that slot. 
 
5. STUDY INTERVENTIONS 
5.1 
Interventions, Administration, and Duration 
Drug Manipulation 
Although not actually an intervention, we will administer naloxone during half of the 
pain induction sessions in order to quantify endogenous opioid (EO) function. We 
will use a placebo-controlled opioid blockade procedure to assess treatment-induced 
changes in EO function, by comparing pain responses under placebo to pain 
responses after opioid blockade with naloxone at pre- and post-treatment. Naloxone 
is an opioid antagonist with a brief half-life (1.1 hours; 78). We will use a weight- 

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adjusted dose of 0.11 mg/kg with a maximum dose of 8mg (8mg dose for a 160 lb. 
individual, consistent with our past work 69-71). As in our past studies, naloxone in 
20 ml normal saline will be infused over a 10-minute period through an intravenous 
cannula placed in the non-dominant arm. At this dosage, naloxone provides effective 
blockade of all three major opioid receptor subtypes (79). Naloxone is FDA 
approved, and appears to have no clinical effects in non-opiate dependent individuals. 
Thus, participants using opioid analgesics on a daily basis or within 3 days of each 
laboratory session (confirmed via urine drug screen) and/or experiences withdrawal 
symptoms with the initial naloxone administration, will be excluded. It has been used 
safely at similar dosages in previous studies, including our studies in CLBP samples 
(68-72). Peak naloxone activity will be achieved approximately 10 minutes following 
completion of the infusion. A second dose of naloxone (0.055 mg/kg with a 
maximum dose of 4mg; 4mg for a 160 lb. individual) will be infused following the 
thermal and ischemic tasks (before CPM procedures). This dose will be used to 
maintain adequate opioid blockade across the duration of pain-induction procedures. 
 
Study Interventions 
Both study treatment interventions will consist of 8 weekly, 1-1.5 hr individual 
sessions. For MT and SMT, the content of each session will be based on a 
standardized treatment manual. Manuals will contain detailed session by session 
information, instructions and scripts for therapists, and patient handouts. 
 
Mindfulness Training (MT) 
Patients will receive training in mindfulness through (a) body scan meditation, a 
gradual moving of attention through the body, accompanied by awareness of 
breathing and other bodily sensations while in a lying position, (b) sitting meditation, 
focusing on awareness of breathing, bodily sensations, thoughts, and emotions, 
practiced sitting on a chair or cushion, (c) gentle movement exercises intended to 
develop awareness (mindfulness) during movement. Each session includes practice of 
these mindfulness techniques. In-session didactic material, interactions and discussion 
on subjects’ experiences of developing and applying mindfulness in everyday life are 
also part of each session. In-session activities include suggestions for application of 
mindfulness as a method for responding positively to stress; dealing with the 
challenges of pain; and exercises focusing on the challenges and achievements 
patients experience in integrating mindfulness into their lives and the stressful 
situations they encounter. Additional discussion will focus on stress reactivity. To 
help patients deal with obstacles to increasing mindfulness, they will be taught 
problem-solving skills to develop solutions to meet MT goals. Finally, patients will 
develop a written maintenance plan that includes a list of short- and long-term goals 
for applying mindfulness methods and a plan for dealing with possible setbacks. 
 
Spinal Manipulation Therapy (SMT) 
SMT sessions will reflect a similar visit pattern and duration as MT sessions. Recent 

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work showed small differences lacking clinical meaningfulness when comparing 
SMT provided 1, 2, or 3 times per week. (88) Furthermore, our visit pattern is 
consistent with professional guidelines (89,90). Thus, we believe our design is 
optimal in matching time required for MT sessions and also meeting effective SMT 
practice patterns. We will administer 2 SMT techniques each session, both of which 
have demonstrated effectiveness and are common for conservative management of 
individuals with CLBP. (37,38,91) See Appendix for description and illustrations. 
We will use scripted interactions between the physical therapist (PT) providing the 
SMT and subjects to stimulate therapist/subject relationships more consistent with the 
relationships that will develop in MT. Each SMT session will be organized as 
follows: 1) Participants will lie on the SMT table for 20 mins, while the PT sits 
approximately 6 ft away. As part of the script, the PT will review with subjects the 
inclusion/exclusion criteria ostensibly to ensure that nothing has changed. 2) The PT 
will perform the 2 SMT techniques during the next 20 mins. 3) Subjects will lie on 
the SMT table for the remaining 20 mins, while the PT sits approximately 6 feet 
away. As part of the script, the PT will ask subjects to perform a posterior pelvic tilt 
exercise. Subjects attempting to enter into discussion of issues beyond the scripted 
plan will be told, ‘‘I’m sorry but because this is a research study I am not allowed to 
discuss this with you.” 
Each individual participant will be in the study for approximately 38 weeks. This 
includes a baseline assessment, 2 pre-treatment laboratory assessments, 8 therapy 
sessions, 2 post-treatment assessments, and 3- and 6-month follow-up visits. 
 
Therapist Training, Adherence, Participant Engagement 
Therapist training. Therapists for MT will be post-doctoral level clinical 
psychologists or other licensed healthcare providers (e.g., nurse practitioner) with 
prior experience delivering MT for chronic pain. Therapists for SMT will be licensed 
PTs. Therapists at Rush and Vanderbilt sites will receive training prior to conducting 
treatment sessions with study subjects. Initial training will consist of a 2-day didactic 
and experiential course conducted by Burns and Carmody for MT and Bialosky for 
SMT. Therapists will be provided detailed manuals and outlines of treatment 
protocols, and the treatment strategies will be taught via direct instruction, recorded 
illustrations of techniques, and role-play of common scenarios. All instruction 
sessions will be digitally videotaped for reference and/or education of new therapists. 
Therapists will be certified to deliver each treatment by having supervisors (i.e., Drs. 
Burns, Carmody and Bialosky) rate tapes of practice role-play sessions prior to their 
working with study subjects. Mastery of each protocol will be required for therapists 
to deliver treatment in the research protocol. 
Procedures to ensure consistency of treatment. To ensure that the therapists 
consistently follow the appropriate treatment protocol, four steps will be taken: (a) 
use of a detailed treatment manual; (b) weekly supervision sessions; (c) audio or 
video recording of sessions for treatment adherence ratings (see below), with these 
recordings and feedback from the adherence raters reviewed during the weekly 
supervision meetings conducted by Burns, Carmody and Bialosky; and (d) provision 

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of therapist feedback on treatment consistency and further didactics and role plays to 
correct “drift” if needed. 
Treatment adherence, and therapist competence. Adherence refers to the extent to 
which a therapist uses interventions prescribed by a protocol. Ratings of adherence to 
the treatments will be conducted by Burns, Carmody, Bialosky and an RA. Protocol 
adherence criteria will be developed for each session with satisfactory adherence 
defined as 90% or more of the maximum possible score on the adherence rating scale. 
Ratings of therapists' competence in delivering the interventions will be used to 
evaluate 20% of the sessions for each of the treatment conditions. Sessions to be 
evaluated will be randomly selected. 
Participant engagement in treatment. Receipt of the intervention by the participant, as 
well as participant perceived difficulty in understanding session content, will be 
assessed via weekly patient engagement checklists after each session. Under 
supervision of Dr. Burns and Bruehl, site RAs will evaluate the checklists for 
consistency. 
5.2 
Handling of Study Interventions 
This is not a study about drug efficacy. However, we will administer naloxone during 
half of the pain induction sessions in order to determine endogenous opioid (EO) 
function. We will use a placebo-controlled opioid blockade procedure to assess 
treatment-induced changes in EO function, by comparing pain responses under 
placebo to pain responses after opioid blockade with naloxone at pre- and post- 
treatment. Naloxone is an opioid antagonist with a brief half-life (1.1 hours; 78). We 
will use a weight-adjusted dose of 0.11 mg/kg with a maximum dose of 8mg (8mg 
dose for a 160 lb. individual, consistent with our past work 69-71). As in our past 
studies, naloxone in 20 ml normal saline will be infused over a 10-minute period 
through an intravenous cannula placed in the non-dominant arm. At this dosage, 
naloxone provides effective blockade of all three major opioid receptor subtypes (79). 
Naloxone is FDA approved, and appears to have no clinical effects in non-opiate 
dependent individuals. It has been used safely at similar dosages in previous studies, 
including our studies in CLBP samples (68-72). Peak naloxone activity will be 
achieved approximately 10 minutes following completion of the infusion. A second 
dose of naloxone (0.055 mg/kg with a maximum dose of 4mg; 4mg for a 160 lb. 
individual) will be infused following the thermal and ischemic tasks (before CPM 
procedures). This dose will be used to maintain adequate opioid blockade across the 
duration of pain-induction procedures. 
MT and SMT treatments will consist of 8 weekly, 1-1.5 hr individual sessions 
delivered by a therapist. For MT and SMT, the content of each session will be based 
on a standardized treatment manual. Manuals will contain detailed session by session 
information, instructions and scripts for therapists, and patient handouts. 
5.3 
Concomitant Interventions 
5.3.1 
Allowed Interventions 
Psychotropic medications and non-opioid analgesic medications are allowed. 

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5.3.2 
Required Interventions 
NA 
5.3.3 
Prohibited Interventions 
Subjects taking daily opiates, even if not dependent, will be excluded from the study 
to avoid precipitating minor withdrawal symptoms. 
Concomitant psychosocial treatments (e.g., cognitive behavioral therapy) and 
physical or manipulation therapies (e.g., PT, chiropractic) are prohibited for this 
study. 
5.4 
Adherence Assessment 
The primary adherence index will be participant attendance of 6 out of the possible 8 
sessions. A secondary adherence index for MT and SMT will be completion of inter- 
session homework assignments. 
 
6. STUDY PROCEDURES 
 
6.1 
Schedule of Evaluations (see table) 

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Pre-Treatment 
Intervention 
Post 
Follow-up 
Session 
Baseline 
Lab 
1 
Lab 
2 
1 
2 
3 
4 
5 
6 
7 
8 
9 
3m 
6m 
Informed Consent 
X 
Demographics (SR) 
X 
Lab 
1 
Lab 
2 
AEI (SR) 
X 
Bothersome Pain Item (SR) 
X 
X* 
X* 
X* 
X* 
X* 
X* 
X* 
X* 
X 
X 
Desirability of Control/Health Locus of 
Control (SR) 
X 
Evoked Pain Intensity and Unpleasantness 
(SR) 
X 
X 
X 
X 
FFMQ-15/MAIA (SR) 
X 
X* 
X* 
X* 
X* 
X* 
X* 
X* 
X* 
X 
X 
Healthcare Utilization (SR) 
X 
X 
X 
X 
Concomitant Medication 
X 
X 
X 
X 
X 
X 
X 
HOME Opioid Questionnaire (SR) 
X 
McGill Pain Questionnaire (SR) 
X 
X 
X 
X 
MPQ (back pain- past week) (SR) 
X 
X 
X 
X 
Oswestry Low Back Disability (SR) 
X 
X 
X 
X 
Pain Catastrophizing Scale (SR) 
X 
X* 
X* 
X* 
X* 
X* 
X* 
X* 
X* 
X 
X 
Pain Self-Efficacy Questionnaire (SR) 
X 
X* 
X* 
X* 
X* 
X* 
X* 
X* 
X* 
X 
X 
PROMIS Anger/Anxiety/Depression/Pain 
Interference & Intensity/Sleep/Physical 
Function/Instrumental Support/Emotional 
Support (SR) 
X 
X* 
X* 
X* 
X* 
X* 
X* 
X* 
X* 
X 
X 
Working Alliance Inventory/Scale to Assess 
Therapeutic Relationship- Patient Version 
X+ 
X+ 
Reaction to Treatment Questionnaire (CEM) 
X 
X+ 
X+ 
Pain Detect Questionnaire (SR) 
X 
Pain Stages of Change Questionnaire (SR) 
X 
X* 
X* 
X* 
X* 
X* 
X* 
X* 
X* 
X 
X 
Naloxone Side Effects (SR) 
X 
X 
X 
X 
Patient Engagement Checklist (completed by 
therapist) 
X 
X 
X 
X 
X 
X 
X 
X 
Spinal Stiffness (before and after session- 
done via Vertetrack) 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 

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Height & Weight (measured by scale) 
X 
Blood Pressure (measured by Dinamap) 
X 
Blood Draw (collected by RN) 
X 
X 
X 
X 
Urine Test (Opioid and Pregnancy-if female) 
X 
X 
X 
X 
Quantitative Sensory Testing 
X 
X 
X 
X 
If applicable: COVID-19 Safety Precautions 
(temperature check, travel history, 
signs/symptoms questionnaire) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
*Survey is done via phone call with research assistant and research assistant enters directly into REDCap or survey is entered directly into 
REDCap online by participant 
+ Survey is done via pen and paper by participant and entered into REDCap by RAs (therapist-blinded) 
SR = self –report. Will be directly entered into REDCap by participant 

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6.2 Description of Evaluations 
COVID-19 PRECAUTIONS FOR STUDY VISITS 
Due to the COVID-19 pandemic (also known as the coronavirus), participants are 
asked to wear a face mask when they come attend study visits. No exceptions are 
allowed. Participants will have their temperature taken upon arrival and will be asked 
to self-screen for signs/symptoms of COVID-19 before coming to their visit. Upon 
arrival, staff may ask these questions again and if the participant is showing any 
signs/symptoms, they will be asked to reschedule their study visit. Study staff 
reserves the right to reschedule appointments if they think participants may be 
showing signs/symptoms of COVID-19. Study staff may add additional screenings 
for participants based on new recommendations and policies from RUMC, VUMC, 
Chicago Public Health Department, Metro Public Health Department, or other 
government agencies. During the COVID-19 pandemic, MT sessions may be 
conducted via Zoom with therapists and participants in separate rooms, but face-to- 
face on an iPad to protect the safety of therapists and participants. 
 
6.2.1 
Phone Screening Evaluation 
Potential participants responding to ads, flyers, etc., will be contacted by phone after 
indicating their desire to be contacted (via e-mail or phone call). They will be asked 
whether they agree to provide basic medical information in order to determine their 
study eligibility. If responding positively, they will be asked whether they have daily 
pain of at least 3 months duration, which is of an average intensity of at least 4/10 
(with 0 being “no pain” and 10 “the worst pain possible”), and presents substantial 
interference in performance of social, work, and everyday activities (≥3/10 on a 10- 
point scale). They will be asked whether: 1) their pain is musculoskeletal pain of the 
lower back and/or leg; 2) they are aged between 18 and 75 years; 3) can understand 
English well enough to complete questionnaires or to participate in therapy; 4) their 
pain is due to malignant conditions, rheumatoid arthritis, complex regional pain 
syndrome, or fibromyalgia syndrome; 5) they have had lumbar surgery within the 
past 6 months or have ever had spinal fusion surgery; 6) they are pregnant; 7) they 
have had liver disease such as hepatitis or cirrhosis; 8) they have osteoporosis; 9) they 
have any active suicidal ideation with intent; 10) they have opioid-dependency or use 
Kratom daily; 11) they can hold their breath for 15 seconds; 12) they have acute 
trauma to spine; 13) they have long term use of corticosteroids; 14) they have a spinal 
cord stimulator, IT pump, or a similar device; 15) they have signs of nerve root 
compression (i.e., positive straight-leg raise <45○); 16) they meet criteria for past or 
present psychotic or bipolar disorders; 17) arthritis of the hand, carpal tunnel 
syndrome, or any neuropathic pain diagnoses affecting the upper limbs; and 18) they 
have a BMI of ≥40. If they meet eligibility criteria, they will be invited to an in- 
person interview. 

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6.2.2 Consent, Detailed Screening, Enrollment, Baseline, and/or Randomization 
Consenting Procedure 
All individuals agreeing to participate will provide written informed consent during 
Visit 1 (i.e., prior to beginning any study procedures). Subject consent procedures 
will be carried out by individuals designated and trained by each site PI and the IRB 
to carry out these procedures (i.e., the proposed research assistants). In the Consent 
Form, it will be emphasized that subjects may discontinue participating at any time 
and still receive prorated compensation. The recruiter will inform potential subjects 
that participation is completely voluntary, and they may withdraw at any time without 
penalty or running the risk of jeopardizing current and future treatment at the Rush or 
Vanderbilt medical centers. Consent forms with identifiable subject information will 
be maintained in a separate locked file from the actual study data files, which will be 
identified only by subject number. All subjects will be informed regarding how 
HIPAA requirements may impact on their study records, and will sign a notification 
regarding this issue. All published data will be reported in a manner in which 
individual data for specific subjects are not identifiable. 
Screening 
Screening can occur from 1 month prior to study enrollment to the day before study 
enrollment. 
Screening evaluations will consist of: 
• demographics 
• confirmation of diagnosis of chronic low back pain 
• pain duration and intensity ratings 
• medical history 
• list of current medications, prescribed dose and reported actual dose taken 
• list of over the counter medications 
• psychological screening: SCID-IV/NP 
Please see sections 4.1 and 4.2 for inclusion/exclusion criteria. The criteria will be 
examined once all screening assessments are complete so as to not alert participants 
to our precise screening criteria. 
Enrollment 
The enrollment date is day the individual has met all the screening criteria and signs 
the informed consent form. 
 
Baseline Assessment (Visit 1) 
• Pain interference (primary outcome), pain intensity, negative affect (anger, 
anxiety, depression), physical function, sleep disturbance and social support will 

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be assessed via designated Patient-Reported Outcomes Measurement Information 
System (PROMIS) forms for each construct. 
• Baseline demographics, neuropathy (painDETECT questionnaire), medication 
and healthcare use, opioid use (HOME Opioid Questionnaire), bothersome pain, 
back pain (McGill Pain Questionnaire) and disability (Oswestry Low Back 
Disability), and attitudes on changing pain (Pain Stages of Change Questionnaire) 
will also be assessed. 
• Pain catastrophizing will be assessed with the Pain Catastrophizing Scale. 
• Mindfulness will be assessed with the Five Facets of Mindfulness Questionnaire 
(short form), and the Multidimensional Assessment of Interoceptive Awareness 
(short form). 
• Self-efficacy will be assessed with the Pain Self-Efficacy Questionnaire. 
• Height and weight will be measured using a scale. 
• Blood pressure will be measured using a Dinamap blood pressure monitor. 
 
Pre-Treatment Lab Sessions (Visits 2 & 3) 
• A urine sample will be collected and tested for opioids (using a rapid single panel 
opioid screening test) and pregnancy (females only – using an analog pregnancy 
test). 
• Baseline assessment of opioid function and conditioned pain modulation will be 
assessed via the Quantitative Sensory Testing (QST) procedures described below. 
• To enable potential future assessment of treatment-related changes in relevant 
biomarkers, a 4mL sample of whole blood will be drawn from the cannula placed 
for drug administration into a tube with EDTA prior to beginning laboratory pain 
or drug administration procedures in both laboratory sessions. Within 10 minutes 
of collection, samples will be centrifuged for 10 minutes at 3500rpm and 4○C. 
Plasma will then be pipetted into microcentrifuge tubes (0.5mL aliquots) and 
stored at -80○C until assayed. 
• McGill Pain Questionnaire administered during the QST procedures in several 
versions to capture pain in back before and after each procedure. 
• Evoked pain intensity and unpleasantness and naloxone side effects will be 
assessed. 
• Assessment of any adverse events. 
 
Endogenous Opioid (EO) Function 
As in our previous work (68-72), we will use a placebo-controlled opioid blockade 
procedure to assess treatment-induced changes in EO function. Naloxone is an opioid 
antagonist with a brief half-life (1.1 hours; 78). We will use a weight-adjusted dose of 
0.11 mg/kg with a maximum dose of 8mg (8mg dose for a 160 lb. individual, 

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consistent with our past work 69-71). As in our past studies, naloxone in 20 ml 
normal saline will be infused over a 10-minute period through an intravenous cannula 
placed in the non-dominant arm. At this dosage, naloxone provides effective blockade 
of all three major opioid receptor subtypes (79). Naloxone is FDA approved, and 
appears to have no clinical effects in non-opiate dependent individuals. Thus, 
participants using opioid analgesics on a daily basis or within 3 days of each 
laboratory session (confirmed via urine drug screen) and/or experiences withdrawal 
symptoms with the initial naloxone administration, will be excluded. It has been used 
safely at similar dosages in previous studies, including our studies in CLBP samples 
(68-72). Peak naloxone activity will be achieved approximately 10 minutes following 
completion of the infusion. A second dose of naloxone (0.055 mg/kg with a 
maximum dose of 4mg; 4mg for a 160 lb. individual) will be infused following the 
thermal and ischemic tasks (before CPM procedures). This dose will be used to 
maintain adequate opioid blockade across the duration of pain-induction procedures. 
The QST protocol will use 2 laboratory pain tasks for evaluation of evoked pain 
responsiveness. An ischemic pain task will be used based on procedures described by 
Maurset et al. (80), similar to our past opioid blockade studies (68,72). Subjects will 
first engage in 2 mins of dominant forearm muscle exercise using a hand 
dynamometer at 50% of his or her maximal grip strength (as determined prior to 
beginning laboratory procedures), and then will be asked to raise the dominant 
forearm over their head for 15 secs. A blood pressure cuff will then be inflated on the 
participant’s dominant biceps to 200 mmHg pressure, and the cuff will remain 
inflated until tolerance is reached, up to a maximum of 8 mins. As in our previous 
work (68,72), at 30-sec intervals throughout the ischemic task, participants will be 
asked to rate their current acute pain using a 0-100 verbal numeric rating scale (0 = 
“no pain” and 100 = “worst possible pain”). Pain threshold will be defined as time 
elapsed from task onset to when the sensation is first described as “painful.” Pain 
tolerance will be defined as time elapsed between onset of the pain task and patients’ 
expressed desire to terminate the task (8 min max). At tolerance, subjects will be 
asked to rate the overall ischemic task pain intensity using the McGill Pain 
Questionnaire (MPQ; see below). 
A heat pain task using a Medoc TSAII NeuroSensory Analyzer (Medoc US., 
Minneapolis, MN) will then follow. This equipment will be used to assess heat pain 
threshold and tolerance using an ascending method of limits protocol as used in our 
prior work (68,71,72). The equipment to be used has a hardware temperature cutoff of 
51○C in order to prevent tissue injury. Four trials each will be conducted for heat pain 
threshold and tolerance, with each trial conducted sequentially at 1 of 4 different non- 
overlapping sites on the non-dominant ventral forearm. An interval of 30 secs 
between successive stimuli will be employed. For threshold trials, the probe will start 
at an adaptation temp of 32○C, with the temp increasing at a ramp rate of 0.5○C/sec 
until the subject indicates that the stimulus has begun to feel “painful.” For tolerance 
trials, the probe will start at an adaptation temperature of 40○C, with the temperature 
increasing at a ramp rate of 0.5○C/sec until the subject indicates maximum tolerance 
has been reached. Means of the 4 thermal pain threshold and tolerance trials will be 
derived for use in analyses. Immediately upon completion of the final heat pain 
tolerance trial, subjects will be asked to rate the overall pain experienced during this 

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trial using the MPQ. EO function will be operationalized as in our past work as 
changes in evoked pain responses between the placebo and naloxone conditions 
(68,71,72), with blockade effects on the visual analog scale (VAS) pain intensity 
measure of the MPQ considered primary. 
 
Conditioned Pain Modulation (CPM) 
Efficiency of descending inhibition of pain (i.e., CPM) will be assessed using a 
protocol adapted from Gehling et al. (81) which found that combining heat pain (test 
stimulus) with cold pressor pain (conditioning stimulus) demonstrated acceptable 
test-retest reliability over a 3 day test-retest interval. CPM is a centrally-mediated 
effect (107), and therefore is expected to be observed at sites throughout the body, 
e.g., CPM elicited with stimuli applied to the back vs. the forearm is similar (102). 
As is common in the CPM literature, and to avoid any local sensitization confounds 
with stimuli applied to the back in CLBP patients, the current project will apply both 
the test and conditioning stimuli in the periphery. A cold pressor task [circulating ice 
water bath; see our prior work (112,113)] applied to the nondominant upper extremity 
will be the tonic conditioning stimulus, and the same TSA-II heat pain stimulus used 
in thermal pain testing (applied to the dominant forearm) will be the test stimulus. At 
the beginning of lab session 1, we will determine the heat pain stimulus temperature 
corresponding with an intensity rating of 60/100 for that individual. This will be done 
using a series of brief (5 sec) thermal stimuli applied starting at 44○C, based on our 
prior work indicating a mean thermal pain threshold and tolerance of 44○C and 48○C 
respectively in chronic back pain patients. This stimulus intensity will be 
increased/decreased incrementally by 0.5○C until the targeted perceived pain 
intensity of 60/100 is reached. This temperature (referred to hereafter as P60) will be 
used as the stimulus intensity for the test stimulus in all CPM procedures. These CPM 
procedures will entail: (a) Three assessments of heat pain ratings (once every 10 sec) 
in response to 30 secs of a constant thermal stimulus applied at the predetermined P60 
target temperature to the dominant arm (“Pre-Conditioning Phase”), (b) Initiation of 
the tonic cold pressor conditioning stimulus to the nondominant hand (immersion in 
an ice water bath) and after 30 sec of exposure to the conditioning stimulus, (c) Three 
assessments of heat pain ratings (once every 10 sec) in response to 30 secs of the P60 
thermal test stimulus applied simultaneously with the conditioning stimulus 
(“Conditioning Phase”; the total cold pressor duration will be 60 seconds). Change in 
mean thermal stimulus pain ratings during the pre-conditioning minus conditioning 
phases will be used to index CPM. 
 
Assessment of spinal stiffness 
The VerteTrack device (VibeDx Diagnostic Corp) will be used to measure the lumbar 
posterior to anterior spinal stiffness, with L3 values considered primary per validation 
studies (40,103). The VerteTrack device has not been approved by the FDA. The 
device consists of a solid aluminum gantry (Width 108cm × Height 109cm × Length 
151cm) on lockable casters that can be positioned over a participant lying in the prone 
position on a standard padded-plinth. Each assessment takes approximately 15 mins. 

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Two types of spinal stiffness values will be calculated from the force displacement 
data of each indentation: global stiffness and terminal stiffness. Global stiffness will 
be calculated from the slope of force displacement curve between 5 Newtons (N) and 
60 N, representing the stiffness of underlying tissues throughout the indentation (39). 
Terminal stiffness is a ratio between the maximal applied force (60 N) and maximal 
resultant displacement, representing stiffness at the end of indentation (39). Spinal 
stiffness will be measured 3 times at each assessment. Averaging 3 measurements, 
within- and between-day reliability point estimates of both global and terminal 
stiffness were 0.99 and 0.98, respectively (40). 
Randomization 
Study subjects will be randomized to receive either MT or SMT. The order of drug 
administration for each laboratory session will also be randomized and 
counterbalanced (placebo vs. naloxone), and double-blinded. These randomizations 
will occur prior to the baseline screening visit (Visit 1). All randomization will be 
carried out using the Proc Plan procedure in SAS version 9.2 (SAS Institute, Cary, 
NC). This SAS procedure will be used to generate a randomization schedule for each 
sequential study slot (MT vs. SMT and the order of naloxone/placebo administration 
in each set of lab visits). Study subjects will be assigned to these previously 
randomized study slots in the order that they are enrolled, and the previously 
determined randomization status associated with each slot will determine the study 
condition each subject is in and the order of drug administration. 
6.2.3 
Blinding 
Research staff at each site who will conduct weekly phone assessments (when 
applicable) and who will conduct the laboratory pain-induction sessions will be blind 
to subject treatment condition. The randomization scheme will be implemented by 
department administrative assistants who will have no other role in the study. 
Given the nature of the interventions and that Co-Is Drs. Carmody and Bialosky will 
be providing intervention-specific oversight (e.g., review of MT and SMT audio- and 
video-recordings), neither of these Co-Is will be blinded as to intervention 
assignment. These individuals will not be engaged in review of individual level study 
data or analysis of study results. The PIs (Drs. Burns and Bruehl) will be blinded to 
intervention assignment. Moreover, during routine review of data, PIs and other 
research staff will also be blinded to participant intervention assignment by hiding 
from view the columns denoting subject ID and intervention status in the REDCap 
database. 
Double blinding (patient and investigators) as to drug condition for all laboratory 
sessions will be maintained by the Investigational Pharmacy at each site. Drug 
blinding will be broken by the PIs for specific participants as needed in the event of 
possible safety or side effect issues. 
Participants will not be blinded to treatment condition: the MT and SMT procedures 
will be obvious. 

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Stake Holder 
Intervention 
Group 
Assignment 
Lab Drug 
Condition 
Primary 
Mechanistic 
Outcome Measure 
Clinical/Functional 
Outcome Measure 
Study Subjects/Patients 
Unblinded 
Blinded 
Unblinded 
Unblinded 
Instructors/Practitioners 
Unblinded 
Blinded 
Blinded 
Blinded 
Outcome Assessors 
Blinded 
Blinded 
Unblinded 
Unblinded 
Statistician 
Blinded 
Blinded 
Unblinded 
Unblinded 
Principal Investigators 
Blinded 
Blinded 
Blinded 
Blinded 
 
 
6.2.4 Treatment Visits 
Treatment Sessions 1-8 (Visits 4, 5, 6, 7, 8, 9, 10, 11) 
• MT and SMT treatments (as assigned) will be conducted during these visits. 
• Assessment of spinal stiffness pre- and post-session as described above. 
• Patient engagement in session will be rated by therapist. 
• Assessment of any adverse events. 
 
Assessed via phone call by RA within 48 hours of session or online via REDCap by the 
patient: 
• Pain interference (primary outcome), pain intensity, negative affect (anger, 
anxiety, depression), physical function, sleep disturbance and social support will 
be assessed via designated PROMIS measures. 
• Pain catastrophizing will be assessed with the Pain Catastrophizing Scale. 
• Mindfulness will be assessed with the Five Facets of Mindfulness Questionnaire 
(short form), and the Multidimensional Assessment of Interoceptive Awareness 
(short form). 
• Self-efficacy will be assessed with the Pain Self-Efficacy Questionnaire. 
• Bothersome pain and attitudes on changing pain (Pain Stages of Change 
Questionnaire) will also be assessed. 
 
Treatment sessions 3 and 6 
In addition to the measures above, the following measures will be given: 
• The Working Alliance Inventory – short form, and the Scale to Assess 
Therapeutic Relationships – Patient Version will be administered in-person. 
• The Reaction to Treatment Questionnaire will be administered in-person. 

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Post-Treatment Lab Sessions (Visits 12, 13) 
• A urine sample will be collected and tested for opioids (using a rapid single panel 
opioid screening test) and pregnancy (females only – using an analog pregnancy 
test). 
• Post-treatment endogenous opioid function and conditioned pain modulation will 
be assessed via the QST procedures described in Section 5.2. 
• To enable potential future assessment of treatment-related changes in relevant 
biomarkers, a 4mL sample of whole blood will be drawn from the cannula placed 
for drug administration into a tube with EDTA prior to beginning laboratory pain 
or drug administration procedures in both laboratory sessions. Within 10 minutes 
of collection, samples will be centrifuged for 10 minutes at 3500rpm and 4○C. 
Plasma will then be pipetted into microcentrifuge tubes (0.5mL aliquots) and 
stored at -80○C until assayed. 
• McGill Pain Questionnaire administered during the QST procedures. 
• Evoked pain intensity and unpleasantness and naloxone side effects will be 
assessed. 
• Assessment of any adverse events. 
 
 
6.2.5 
Follow-up Visits 
Follow-ups 3-month & 6-month (Visits 14 & 15) 
• 
Pain interference (primary outcome), pain intensity, negative affect (anger, 
anxiety, depression), physical function, sleep disturbance and social support will 
be assessed via PROMIS item banks. 
• 
Pain catastrophizing will be assessed with the Pain Catastrophizing Scale. 
• 
Mindfulness will be assessed with the Five Facets of Mindfulness Questionnaire 
(short form), and the Multidimensional Assessment of Interoceptive Awareness 
(short form). 
• 
Self-efficacy will be assessed with the Pain Self-Efficacy Questionnaire. 
• 
Bothersome pain and attitudes on changing pain (Pain Stages of Change 
Questionnaire) will also be assessed. 
• 
Assessment of any adverse events. 
6.2.6 
Missed Evaluations 
There is a 6-week window from baseline (visit 1) to the first lab session (visit 2). The 
first lab session (visit 2) must occur within this window and the second lab session 
(visit 3) must be within 2 weeks of the first. The first treatment visit (visit 4) is to 

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occur within one week from lab session 2 (visit 3). 
If a participant misses an intervention session (MT or SMT) the staff will attempt to 
reschedule the visit for the following week, and the treatment schedule will be 
adjusted accordingly. 
Treatment sessions 1-4 (visits 4-7) must all occur within 2 months of lab session 2 
(visit 3). The first post-treatment lab session (visit 12) should occur within one month 
from treatment session 8 (visit 11). 
The second post treatment lab session (visit 13) must occur within 2 weeks of the first 
post treatment lab session (visit 12). 
The date of the follow-up assessments will be calculated from the date of the final 
post treatment lab session (visit 13). Participants will have a 2-week window around 
this date to complete the 3- and 6-month follow-ups (visits 14 & 15). Failure to 
complete these assessments within this window will result in the follow-ups being 
skipped. 
All visits that fall outside of these allowable windows will be reported as protocol 
deviations. 
 
7. SAFETY ASSESSMENTS 
People with chronic pain who begin completing frequent assessments of current pain, 
mood and activity levels may report increased awareness of their pain and distress. 
Participants will be told that such phenomena associated with close self-monitoring 
are a part of the treatment approaches we are offering, and will be addressed as part 
of the interventions. However, participants will be closely monitored (by the study 
coordinator/RA who will report relevant observations to the site PIs) during the study 
for significant increases in pain intensity and negative mood, and if any are noted, 
participants will be contacted to discuss these issues with the site PI. As appropriate, 
they will be referred by the site PI to their physician for further evaluation should 
there be any unexpected or significant deleterious changes. Participants will also be 
monitored as above during the course of the study for evidence of significant 
emotional problems. Any participant judged to be deteriorating significantly in terms 
of psychological and pain condition as a result of their participation in this study will 
be withdrawn from the trial and referred for individual treatment. 
Therefore, a standardized referral form is not considered adequate for this study. The 
site PI will personally monitor all such referrals and document them accordingly. 
Such documentation will be kept confidential in the locked data storage area. 
7.1 
Specification of Safety Parameters 
During the assessment phase, and/or during the treatment phase, should any 
participant report significant physical or emotional distress or other adverse event, the 
site PI will be notified immediately. The site PI will contact the participant by 
telephone, assess the event, and determine whether referrals to other healthcare 
providers are appropriate. Any necessary referrals will be made through telephone 
contact by the site PI to the appropriate practitioner. 

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7.2 
Methods and Timing for Assessing, Recording, and Analyzing Safety 
Parameters 
Diligent study safety monitoring will be conducted by the PIs on an ongoing basis, in 
conjunction with the IMC, the IRB and NCCIH as appropriate (see above). Study 
progress and safety will be reviewed weekly by the PIs. Progress reports, including 
patient recruitment into the full study, and adverse events (AEs) will be provided to 
the Independent Monitoring Committee (IMC) each quarter. This quarterly IMC 
progress report will be submitted to the IMC on January 15, April 15, July 15, and 
October 15. The more detailed semi-annual report will be submitted to the IMC on 
January 15 and July 15. A separate report will be compiled every 6 months and will 
include a list and summary of AEs. In addition, the report will address (1) whether 
adverse event rates are consistent with pre-study assumptions; (2) reason for dropouts 
from the study; (3) whether all subjects met entry criteria; (4) whether continuation of 
the study is justified on the basis that additional data are needed to accomplish the 
stated aims of the study; and (5) conditions whereby the study might be terminated 
prematurely. The IMC report prepared every 6 months will be signed by the members 
of the IMC and will be forwarded to the IRBs and NCCIH (reports will be provided 
more frequently on an ongoing basis if concerns are identified). The IRBs will review 
progress of this study on an annual basis. 
 
Before the study begins, all subjects will be provided with contact phone numbers for 
research staff so that subjects can contact study staff at any time during the study. 
When in the laboratory, subjects will be supervised continuously. During the study, 
the PIs will monitor all adverse events, defined as any unfavorable or unintended 
symptom, sign or disease associated with a medical treatment or procedure that may 
or may not be related to the treatment or procedure. Part of this process will include 
monitoring of serial phone/online assessments by the research coordinator/RAs for 
worsening of physical or mental health during study participation. Adverse events can 
be related to participation in the study or to medical or psychiatric conditions being 
treated (e.g. depression), or they could be entirely unrelated to any of these (e.g., 
motor vehicle accident). In this study, we will use the FDA definition of serious 
adverse events (SAE; e.g., death, hospitalization, emergency room visits, suicide 
plans or attempts). SAEs will be systematically assessed at each lab visit. Any SAE, 
whether or not related to study intervention, will be immediately reported to the IRB 
and the NCCIH. Review by the IMC, IRB and NCCIH regarding the nature of the 
SAE will be used to decide whether the study should continue as is, whether changes 
to protocol are needed, or whether the study must be discontinued. 
7.3 
Adverse Events and Serious Adverse Events 
To ensure the safety of trial participants, we will monitor all adverse events, defined 
as any unfavorable or unintended symptom, sign or disease associated with a medical 
treatment or procedure that may or may not be related to the treatment or procedure. 
Adverse events can be related to the treatment or to the disorder being treated (e.g. 
pain exacerbation), as well as to a concurrent disorder or treatment (e.g. diabetes or 

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its treatment), or they could be entirely unrelated to any of these (e.g., motor vehicle 
accident). 
In this study, we will use the FDA definition of serious adverse events (SAE, e.g., 
death, hospitalization, emergency room visits, suicide plans or attempts). 
A Serious Adverse Event (SAE) is any AE that results in one or more of the 
following outcomes: 
• 
Death 
• 
A life-threatening event 
• 
Inpatient hospitalization or prolongation of existing hospitalization 
• 
A persistent or significant disability/incapacity 
• 
A congenital anomaly or birth defect 
• 
Important medical event based upon appropriate medical judgment 
7.4 
Reporting Procedures 
SAEs will be systematically assessed at each treatment session. Any SAE, whether or 
not related to study intervention, will be reported to the IMC and the IRB, as well as 
NCCIH on an ongoing basis. In addition, the PIs will prepare a semi-annual report on 
data collection and occurrence of any SAE for review by the IMC and IRBs. The 
initial SAE report will be followed by submission of a completed resolution report to 
the IRBs and the IMC. 
Solicited events will occur as part of the weekly phone calls/online assessments 
during the treatment epoch. 
Unsolicited events will occur when a participant contacts study staff to report a 
worsening in their symptomatology, and when pain and mood data during the 
intervention is compared to baseline. 
SAEs that are unanticipated, serious, and possibly related to the study intervention 
will be reported to the IMC, IRB and NCCIH in accordance with requirements. 
Unexpected fatal or life-threatening AEs related to the intervention will be reported to 
the NCCIH Program Officer within 7 days. Other serious and unexpected AEs related 
to the intervention will be reported to the NCCIH Program Official within 15 days. 
Anticipated or unrelated SAEs will be handled in a less urgent manner but will be 
reported to the IMC, IRBs, NCCIH, and other oversight organizations in accordance 
with their requirements. In the annual AE summary, the IMC Report will state that 
they have reviewed all AE reports. 
7.5 
Follow-up for Adverse Events 
In the event that a participant withdraws from the study or the investigator decides to 
discontinue a patient due to SAE, the patient will be monitored by the PIs via ongoing 
status assessment until (1) a resolution is reached (i.e., the problem has resolved or 
stabilized with no further changes expected), (2) the SAE is determined to be clearly 

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unrelated to the study intervention, or (3) the SAE results in death. Review by the 
IMC, IRB and NCCIH regarding the nature of any SAE will be used to decide 
whether the study should continue as is, whether changes to protocol are needed, or 
whether the study must be discontinued. In this case, the PI and Co-PI will discuss 
any proposed changes or study termination with the NCCIH Program Officer. We 
will also monitor safety alerts, defined as events that are relevant to the study 
populations and pose safety risks to study participants. Examples of safety alerts 
would include a sudden increase in pain symptoms or change in the type of pain 
experienced, or a clinically significant increase in patient depression or anxiety. Both 
SAEs and safety alerts will be tracked using a standardized form recording the date of 
the event, type of event, attribution of the event (e.g., judgment regarding whether it 
was intervention related), whether the event was resolved or controlled, and the 
resolution date. Any concerns identified will be reported to NCCIH and the IRB on 
an ongoing basis. 
7.6 
Safety Monitoring 
Safety of participants will be ensured by the continued monitoring of their mental 
health and medical status. Subjects will all have access to treatment-as-usual services 
to address any study-induced adverse effects or other clinical concerns. We propose a 
Data Safety and Monitoring Committee (IMC) in which outside safety officers will 
oversee all implementation and data collection issues related to project safety in 
addition to careful IRB and PI monitoring. The IMC will be established external 
researchers who are experienced in the safe conduct of randomized controlled trials. 
They will monitor all data- and safety-related procedures and ensure participant 
safety during the study. The PIs will provide periodic updates (minimally, once per 
month) to the safety officers on study performance. 
The proposed IMC is described in the DSMP document. All three monitors are not 
associated with this research project and thus work independently of the PIs, Dr. 
Bruehl and Dr. Burns. All three monitors are not part of the key personnel involved in 
this grant. 
Study progress and safety will be reviewed quarterly (and more frequently if needed). 
Progress reports, including patient recruitment, retention/attrition, and AEs will be 
provided to the Independent Monitor(s) following each of the quarterly reviews. An 
Annual Report will be compiled and will include a list and summary of AEs. In 
addition, the Annual Report will address (1) whether AE rates are consistent with pre- 
study assumptions; (2) reason for dropouts from the study; (3) whether all participants 
met entry criteria; (4) whether continuation of the study is justified on the basis that 
additional data are needed to accomplish the stated aims of the study; and (5) 
conditions whereby the study might be terminated prematurely. The Annual Report 
will be sent to the IMC and will be forwarded to the IRB and NCCIH. The IRB and 
other applicable recipients will review progress of this study on an annual basis. The 
PIs will also send copies of signed recommendations and comments from the IMC to 
the NCCIH Program Officer within 1 month of each monitoring review. 

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8. INTERVENTION DISCONTINUATION 
This study will be stopped prior to its completion if: (1) the intervention is associated 
with adverse effects that call into question the safety of the intervention; (2) difficulty 
in study recruitment or retention will significantly impact the ability to evaluate the 
study endpoints; (3) any new information becomes available during the trial that 
necessitates stopping the trial; or (4) other situations occur that might warrant 
stopping the trial. 
Other potential reasons for early termination may include individual participant gross 
noncompliance (e.g., not responding to phone calls from staff, several cancellations 
of treatment appointments, no-shows to treatment appointments). Participants will 
also be discontinued if study investigators see a >25% worsening of baseline pain and 
mood during the MT or SMT treatments. 
Participants will be monitored during the course of the study for evidence of 
significant deleterious physical, pain-related or emotional changes. In the event that a 
participant is judged by the research assistants and/or PIs to be deteriorating 
significantly in terms of pain and emotional condition as a result of their participation 
in this study, the team may decide to withdraw the subject from the trial and refer 
them for appropriate treatment. Participants will also be informed that should any 
unexpected or significant deleterious changes in their condition occur, that they 
immediately call Dr. Burns or Dr. Bruehl (PhD licensed clinical psychologists). 
Subjects will be given the office phone numbers of Drs Burns and Bruehl to ensure 
access to study staff. Drs. Burns and Bruehl will determine whether referrals to other 
healthcare providers are appropriate. Any necessary referrals will be made through 
telephone contact by the PIs to the appropriate practitioner. Therefore, a standardized 
referral form is not considered adequate for this study. The PIs will personally 
monitor all such referrals and document them accordingly. Such documentation will 
be kept confidential in the locked data storage area in Drs. Burns’ or Bruehl’s office. 
 
If a participant experiences a SAE, he/she will be discontinued in the study. 
 
For the purposes of intent-to-treat analyses, we will make every effort to obtain 
scheduled follow-up assessments for all individuals failing to complete the study for 
any reason. 
 
If NCCIH asks us to discontinue the study, we will discontinue all participants. If the 
study intervention is discontinued we will continue to follow participants for 1-month 
post intervention, with their permission. As planned for the follow up period, 
participants will be asked to rate their pain, function and mood. 
 
There will be no cases of temporary discontinuation of treatment. 

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9. STATISTICAL CONSIDERATIONS 
9.1 
General Design Issues 
This comparative mechanism study will compare the degree to which 2 distinct C/I 
interventions, MT vs. SMT, activate specific and non-specific mechanisms, and the 
degree to which these mechanisms affect pain-related outcomes. Comparing the role 
of diverse mechanisms in outcomes of these 2 interventions in a single RCT will 
permit testing the extent to which various mechanistic effects are shared across 
treatments vs. unique to a given treatment. Two hundred eighty-six people (to achieve 
240 completed participants assuming 16% dropout) with CLBP will be randomly 
assigned to MT or SMT. These interventions were chosen because: a) RCT data 
already support their efficacy; b) their hypothesized specific mechanisms of action 
are quite distinct; c) they vary regarding the degree of active vs passive patient 
participation required; d) their use is widespread and growing. All mechanisms and 
outcomes will be assessed frequently across all treatments. We expect both treatments 
to produce significant changes in pain, mood and function. 
Aim 1: Test effects of 2 treatments on non-specific mechanisms. We will test to what 
degree MT and SMT produce changes in the 3 categories of non-specific 
mechanisms: endogenous pain inhibitory systems (endogenous opioid function; 
conditioned pain modulation), pain-related cognition (pain catastrophizing; self- 
efficacy), and therapy factors (therapeutic relationship, patient expectations). We 
hypothesize that MT and SMT will produce changes in these non-specific 
mechanisms to approximately the same degree. 
Aim 2: Test effects of 2 treatments on specific mechanisms. We will test to what 
degree MT and SMT produce changes in treatment-specific mechanisms (MT: 
changes in how patients think about pain; SMT: spinal stiffness). We expect that MT 
and SMT will each affect their own treatment-specific mechanism more than will the 
other treatment (e.g., MT will produce larger changes in mindfulness than SMT; SMT 
will produce larger changes in spinal stiffness than MT). 
Aim 3: Test relative predictive validity of non-specific and specific mechanisms. We 
will test to what degree changes in non-specific and specific mechanisms predict 
changes in pain, mood and function, and whether these relationships depend on the 
treatment received. We will first test Mechanism Change x Treatment interactions to 
determine whether changes in any candidate mechanisms predict outcomes to a 
greater degree in one treatment than the other. In the absence of interactions, we will 
test the degree to which changes in non-specific and specific mechanisms account for 
unique and shared variance in predicting outcomes. 
Aim 4: To address competing causation paths, we will test lagged and cross-lagged 
effects of early-treatment changes in non-specific and specific mechanisms predicting 
late-treatment changes in outcomes. 
9.2 
Sample Size and Randomization 
Power consideration for Aim 1: 

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Based on past findings, we expect that Mindfulness Training (MT) and Spinal 
Manipulation Therapy (SMT) will have near-equivalent effects on the primary 
outcome, changes in EO function. We ran power calculations assuming a true 
difference of 0 between MT and SMT. Please note that we plan to enroll 286 
participants to achieve a sample size of 240 completed participants. See below: 
 
Power Analysis of Two-Sample T-Test for Testing Equivalence Using Differences 
 
MT 
Group 
Sample 
SMT 
Group 
Sample 
Lower Upper 
Power 
Size 
(N1) 
Size 
(N2) 
Equiv. 
Equiv. 
Limit 
Limit 
True 
Difference 
Standard 
Deviation 
Alpha 
Beta 
0.851 
120 
120 
-3.0 
3.0 
0.0 
7.5 
0.050 
0.149 
0.950 
120 
120 
-3.5 
3.5 
0.0 
7.5 
0.050 
0.050 
0.987 
120 
120 
-4.0 
4.0 
0.0 
7.5 
0.050 
0.013 
 
An equivalence test of means using two one-sided tests on data from a parallel-group 
design with sample sizes of 120 in the reference group and 120 in the treatment group 
achieves 85% power at a 5% significance level when the true difference between the 
means is 0.0, the standard deviation is 7.5, and the equivalence limits are -3.0 and 3. 
 
Power considerations for Aim 2: 
 
We will test effects of MT and SMT on the treatment-specific mechanisms, pre-post 
treatment changes in mindfulness and spinal stiffness. Per reviewer suggestions and 
input from our co-I, Dr. Carmody, we expanded the assessment of “mindfulness” to 
include pain unpleasantness/bothersome ratings and the 
Multidimensional Assessment of Interoceptive Awareness (MAIA) scale as well as 
the Five Facets of Mindfulness Questionnaire (FFMQ). We expect MT to produce 
larger changes in the mindfulness measures than SMT, and for SMT to produce larger 
changes in spinal stiffness than MT. 
 
Null Hypothesis: Mean1=Mean2. Alternative Hypothesis: Mean1<>Mean2 
 
Allocation 
Power 
N1 
N2 Ratio 
Alpha 
Beta 
Mean1 
Mean2 
S1 
S2 
0.800 
120 120 
1.0 
0.050 
0.200 
0.36 
0.00 
1.00 
1.00 
0.983 
120 120 
1.0 
0.050 
0.017 
0.53 
0.00 
1.00 
1.00 

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Treatment group sample sizes of 120 and 120 will achieve 80% power to detect a 
difference of Cohen’s d = 0.36. With a larger effect – d = .53 -- at α=0.05 we will 
have 98.3% power to detect a treatment difference. 
 
Power considerations for Aim 3: 
 
The first focus is to determine whether pre-post changes in specific and non-specific 
mechanisms (e.g., specific: spinal stiffness changes; non-specific: self-efficacy 
changes) interact with Treatment Condition to predict pre-post changes in DVs (e.g. 
pain intensity changes). A significant interaction would suggest that pre-post changes 
in a mechanism factor predicted pre-post changes in a DV differently depending on 
Treatment Condition. In the case of a significant interaction, we will test simple 
slopes of pre-post mechanism changes for DV changes for each Treatment Condition 
separately. We do not expect many significant interactions. Thus, we focus our power 
analyses on detecting increments in R2 when adding pre-post mechanism change 
scores into regressions to predict pre-post changes in outcomes. 
 
Multiple Regression Power Analysis 
 
Power 
N of independent variables teste R2 for Independent 
Variable(s) tested 
R2 for Variables controlled 
0.74152 
1 
0.025 
0.1 
0.81731 
1 
0.030 
0.1 
0.79137 
1 
0.025 
0.2 
0.86115 
1 
0.030 
0.2 
0.84360 
1 
0.025 
0.3 
0.90403 
1 
0.030 
0.3 
All calculations assume N=240 and α=0.05. Again note that we expect to 
recruit 286 subjects to achieve an analyzable sample of 240 completed 
subjects. 
 
With 10% of variance in pre-post outcome changes accounted by mechanism 
variables already in the equation, we have 74% power to detect a 2.5% 
increment in R2 with the addition of another mechanism variable. This 
increases to 90% power to detect a 3% increment in R2 when mechanism 
variables already in the equation account for 30% of the outcome changes. 
Note that these power analyses for Aim 3 were based on testing the 
association between changes in EO function and changes in pain interference. 

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Treatment Assignment Procedures 
Study patients will be randomized to receive either MT or SMT. The order of drug 
administration for each laboratory session will also be randomized and 
counterbalanced (placebo vs. naloxone), and double-blinded. All randomization will 
be carried out using the Proc Plan procedure in SAS version 9.2 (SAS Institute, Cary, 
NC). This SAS procedure will be used to generate a randomization schedule for each 
sequential study slot (MT vs. SMT and the order of naloxone/placebo administration 
in each set of lab visits). Study subjects will be assigned to these previously 
randomized study slots in the order that they are enrolled, and the previously 
determined randomization status associated with each slot will determine the study 
condition each subject is in and the order of drug administration. 
 
The research assistants (RA) at each site who will conduct weekly phone assessments 
(when applicable) and who will conduct the laboratory pain-induction sessions will 
be blind to subject treatment condition. The randomization scheme will be 
implemented by department administrative assistants who will have no other role in 
the study. 
 
Given the nature of the interventions and that Co-Is Drs. Carmody and Bialosky will 
be providing intervention-specific oversight (e.g., review of MT and SMT audio- and 
video-recordings), neither of these Co-Is will be blinded as to intervention 
assignment. These individuals will not be engaged in review of individual level study 
data or analysis of study results. The PIs (Drs. Burns and Bruehl) will be blinded to 
intervention assignment. Moreover, during routine review of data, PIs and other 
research staff will also be blinded to participant intervention assignment by hiding 
from view the columns denoting subject ID and intervention status in the REDCap 
database. 
 
Double blinding (patient and investigators) as to drug condition for all laboratory 
sessions will be maintained by the Investigational Pharmacy at each site. Drug 
blinding will be broken for specific participants as needed in the event of possible 
safety or side effect issues. This unblinding will be done by the site PIs in conjunction 
with investigational pharmacists. 
 
Participants will not be blinded to treatment condition: the MT and SMT procedures 
will be obvious. 
 
 
Stake Holder 
Intervention 
Group 
Assignment 
Lab Drug 
Condition 
Primary 
Mechanistic 
Outcome Measure 
Clinical/Functional 
Outcome Measure 
Study Subjects/Patients 
Unblinded 
Blinded 
Unblinded 
Unblinded 
Instructors/Practitioners 
Unblinded 
Blinded 
Blinded 
Blinded 
Outcome Assessors 
Blinded 
Blinded 
Unblinded 
Unblinded 
Statistician 
Blinded 
Blinded 
Unblinded 
Unblinded 

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Principal Investigators 
Blinded 
Blinded 
Blinded 
Blinded 
 
9.3 
Definition of Populations 
The ITT (intent to treat) sample will be all subjects who complete baseline measures. 
The “per protocol” sample (i.e., “treatment completers”) will be those subjects who 
complete at least 6 of the 8 treatment sessions. 
9.4 
Interim Analyses and Stopping Rules 
We do not plan to conduct interim analyses. 
Findings that would trigger a safety review are two or more occurrences of a 
particular type of SAE, severe AEs/reactions, or increased frequency of events. The 
site PIs would present them to the IMC statistician to review the events by group to 
determine whether there are statistical as well as clinical concerns. The statistician 
reports his findings to a closed session of the IMC and/or NCCIH. The findings are 
used to determine what steps will be taken. 
9.5 
Outcomes 
In Aims 1 and 2, our goal is to test the degree to which MT and SMT change specific 
and non-specific mechanisms. Thus, we will assess pre-post treatment changes in 
mindfulness and spinal stiffness (specific mechanisms), and in endogenous opioid 
(EO) function, CPM, pain-related cognition and therapy factors (non-specific 
mechanisms). For the sake of analyses for Aims 1 and 2, changes in these variables 
are “outcomes.” The primary mechanism outcome is change in EO function. 
In Aim 3, our goal is to determine the degree to which treatment-induced changes in 
mechanisms are related to treatment-induced changes in the pain, mood and function 
dependent variables. Prior to the multiple variate analyses, we will determine the 
degree to which MT and SMT affect pre-post changes in the primary dependent 
variable, “pain interference” and in secondary dependent variables (mood and 
function). Our primary goal in this project is to ascertain the degree to which MT and 
SMT alter putative mechanisms of action. Change in pain interference is the primary 
dependent variable, reflecting treatment effects, which will be predicted by change in 
mechanism factors. 
Aim 1: Test effects of 2 treatments on non-specific mechanisms. The primary 
objective is to test to what degree MT and SMT produce changes in the 3 categories 
of non-specific mechanisms. The primary endpoints depend on the particular 
mechanism being examined: endogenous opioid function, conditioned pain 
modulation, pain-related cognition, and therapy factors. Analyses are described in 
detail below. 
Aim 2: Test effects of 2 treatments on specific mechanisms. The primary objective is 
to test to what degree MT and SMT produce changes in treatment-specific 
mechanisms. The primary endpoints depend on the particular mechanism being 
examined: changes in mindfulness and spinal stiffness. Analyses are described in 
detail below. 

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Aim 3: Test relative predictive validity of non-specific and specific mechanisms. The 
primary objective is to test to what degree changes in non-specific and specific 
mechanisms predict changes in pain, mood and function, and whether these 
relationships depend on the treatment received. We will first test Mechanism Change 
x Treatment interactions to determine whether changes in any candidate mechanisms 
predict outcomes to a greater degree in one treatment than the other. In the absence of 
interactions, which we expect to be largely the case, we will test the degree to which 
changes in non-specific and specific mechanisms account for unique and shared 
variance in predicting outcomes. 
Aim 4: To address competing causation paths. The primary objective is to test lagged 
and cross-lagged effects of early-treatment changes in non-specific and specific 
mechanisms predicting late-treatment changes in outcomes. Analyses are described in 
detail above. 
9.5.1 
Primary Outcome 
Our primary mechanism outcome is pre- to post treatment changes in EO function. 
9.5.2 
Secondary Outcomes 
Secondary outcomes are pre-post treatment changes in mindfulness and spinal 
stiffness (specific mechanisms), and in CPM, pain-related cognition and therapy 
factors (non-specific mechanisms). Other secondary outcomes refer to pre-post 
changes in patient reported clinical status. These are pain intensity, negative affect 
(anger, anxiety, depression), physical function, sleep disturbance and social support 
assessed via PROMIS item banks. 
9.6 
Data Analyses 
Primary analyses will be conducted on an ITT basis. 
 
Aim 1: To determine the degree to which MT and SMT produce effects in 
nonspecific mechanisms. 
 
The primary analyses will employ the two-sample t-test to compare mean change in 
each nonspecific mechanism within a noninferiority test construct to compare mean 
change in outcome from pre to post treatment between the two treatment arms. An 
overall, 2-sided, significance level of 0.05 will be used. Linear mixed models will be 
used as a supplemental analysis, allowing us to utilize all data collected, account for 
within subject variation, and model changes over time. The fixed effect part of the 
model will be 
Mechanismij= β0 + β1Timeij + β2Txi + β3(Txi*Timeij) + εij for subject i at visit j. 
If β3 is significantly negative (p <.05), this would indicate that the mechanism 
variable decreased more in SMT than in MT (Fitzmaurice, Laird, & Ware, 2011). In 
case of a significant interaction, we will test simple slopes of Time for each 
Treatment Condition separately AND by testing post treatment differences between 
MT and SMT controlling for pre-treatment values. 

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Candidate covariance structures will be assessed using the data’s correlation structure 
and Akaike’s Information Criterion (AIC). Random coefficients (e.g. random 
intercept and/or random slope) will be included in the model if they significantly 
improve the model fit as determined by the likelihood ratio test. Standardized 
residuals and Cook’s distance will be used to assess the influence of outliers and 
individual observations. Residual plots will be used to check the multivariate normal 
distribution assumption. The pattern of missing data will be examined to determine its 
missing mechanism and the amount. If data are missing not at random (MNAR), data 
imputations may be used. If other deviations from the model assumptions are 
detected, appropriate measures will be taken to prevent inferential bias, e.g. data 
transformations and use of bootstrap techniques to compute standard errors. 
Potential covariates (site, age, and any baseline variables found to be significantly 
different (p < .20) between treatment groups) will be considered for model inclusion 
using a model selection method called least absolute shrinkage and selection operator 
(LASSO) (Tibshirani, 2011). This method identifies groups of covariates to form a 
parsimonious model; it avoids problems in stepwise procedures such as collinearity, 
bias, and variance deflation (Flom & Cassell, 2007); the method has recently been 
extended to mixed effects models (Bondell, Krishna, & Ghosh, 2010; Fan & Li, 2012; 
Fernandez, 2007). 
 
Aim 2: To determine whether MT will produce greater improvements in 
mindfulness-related factors than SMT, and whether SMT will produce greater 
improvements in spinal stiffness than MT. 
 
The primary analyses will employ the two-sample t-test to compare mean change in 
each specific mechanism to compare mean change in outcome from pre to post 
treatment between the two treatment arms. An overall, 2-sided, significance level of 
0.05 will be used. Linear mixed models will be used as a supplemental analysis, 
allowing us to utilize all data collected, account for within subject variation, and 
model changes over time. The fixed effect part of the model will be 
Mechanismij= β0 + β1Timeij + β2Txi + β3(Txi*Timeij) + εij for subject i at visit j. 
If β3 is significantly negative (p <.05), this would indicate that the mechanism 
variable decreased more in SMT than in MT (Fitzmaurice, Laird, & Ware, 2011). In 
case of a significant interaction, we will test simple slopes of Time for each 
Treatment Condition separately AND by testing post treatment differences between 
MT and SMT controlling for pre-treatment values. As in Aim 1, we will follow this 
analysis with generalized linear mixed effects modeling (GLMM) with subject- 
specific intercepts and subject-specific slopes. 
Candidate covariance structures will be assessed using the data’s correlation structure 
and Akaike’s Information Criterion (AIC). Random coefficients (e.g. random 
intercept and/or random slope) will be included in the model if they significantly 
improve the model fit as determined by the likelihood ratio test. Standardized 
residuals and Cook’s distance will be used to assess the influence of outliers and 
individual observations. Residual plots will be used to check the multivariate normal 
distribution assumption. The pattern of missing data will be examined to determine its 

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missing mechanism and the amount. If data are missing not at random (MNAR), data 
imputations may be used. If other deviations from the model assumptions are 
detected, appropriate measures will be taken to prevent inferential bias, e.g. data 
transformations and use of bootstrap techniques to compute standard errors. 
Potential covariates (site, age, and any baseline variables found to be significantly 
different (p < .20) between treatment groups) will be considered for model inclusion 
using a model selection method called least absolute shrinkage and selection operator 
(LASSO) (Tibshirani, 2011). This method identifies groups of covariates to form a 
parsimonious model; it avoids problems in stepwise procedures such as collinearity, 
bias, and variance deflation (Flom & Cassell, 2007); the method has recently been 
extended to mixed effects models (Bondell, Krishna, & Ghosh, 2010; Fan & Li, 2012; 
Fernandez, 2007). 
 
Aim 3: To test the relative predictive validity of non-specific and specific 
mechanisms. 
 
To test to what degree changes in non-specific and specific mechanisms predict 
changes in pain, mood and function, and whether these relationships depend on the 
treatment received, we will first test Mechanism x Treatment interactions to 
determine whether changes in any of the candidate mechanisms predict outcomes to a 
greater degree in one treatment over the other. Linear mixed effects regression 
models will be conducted to test, for example, a non-specific mechanism change 
score x Treatment interaction for each outcome change. If significant differences are 
observed, then the interaction effects will be interpreted to provide the unique effect 
of mechanism change for each treatment group. 
 
In the absence of interactions, we will use linear mixed effects regression models to 
test the degree to which changes in non-specific and specific mechanisms account for 
unique and shared variance in pre-post outcome changes. More specifically, 0-order 
correlations among mechanism and outcome pre-post change scores will reveal 
“candidate” mechanisms (i.e., those with significant associations with pre-post 
outcome changes). We will use a series of hierarchical regressions to examine the 
degree to which ostensibly different mechanisms account for shared or unique 
variance in outcome changes. Such analyses will allow us to identify common areas 
of mechanism overlap (e.g., changes in self-efficacy and pain catastrophizing 
accounting for much shared variance in pain changes), and mechanism uniqueness 
(e.g., changes in spinal stiffness accounting for significant unique variance in pain 
changes even with other mechanism changes controlled). 
 
Aim 4: Address competing causation pathways. 
 
First, we will use an approach and techniques that we have used in previous 
publications [eg, Burns, J.W., Nielson, W.R., Jensen, M.P., Heapy, A., Czlapinski, R., 
& Kerns, R.D. (2015). Specific and general therapeutic mechanisms in cognitive- 
behavioral treatment of chronic pain. Journal of Consulting and Clinical 
Psychology.83, 1-11. PMID: 24979313]. Namely, we will test lagged and cross- 

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lagged effects using pre- to mid-treatment and mid- to post-treatment epochs. Given 
that endogenous opioid functioning will be assessed only at pre-and post-treatment, 
and given that the working alliance and subject expectations for benefit will be 
assessed only at 3- and 6-weeks, this approach will allow to examine comparable 
effects across all our specific and non-specific mechanisms. Residual change scores 
for all mechanism and outcome variables will be computed by regressing mid- 
treatment on pre-treatment values (i.e., a pre-mid residual change score), and 
regressing post-treatment on mid-treatment values (i.e., mid-post residual change 
score). For lagged relationships, regressions will be performed to identify the unique 
effect of pre-mid mechanism changes on mid-post outcome changes. This will 
require statistically controlling for the path from pre-mid mechanism change to mid- 
post mechanism change and pre-mid outcome change to mid-post outcome change. 
See Figure 1 and 2 below. The red line is the target lagged effect. The two blue lines 
are the paths to be controlled. 

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Figure 1 
 
 
Figure 2 

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For cross-lagged effects, the procedure will be inverted. Namely, we will test whether 
pre-mid changes in outcomes predict mid-post changes in mechanisms. Significant 
lagged effects paired with non-significant cross-lagged effects will add support to the 
notion that early-treatment changes in putative mechanisms influenced later-treatment 
changes in outcomes. In general, we expect that pre-mid changes in mindfulness and 
spinal stiffness will predict mid-post changes in pain interference (and other 
outcomes), but the inverse will not be the case. 
 
Second, we will take a more fine-grained HLM approach using the weekly data. We 
will test whether: a) previous week levels of specific (e.g., mindfulness, spinal 
stiffness) and nonspecific mechanisms (e.g. self-efficacy) predict previous week to 
next week changes in outcomes; b) these relationships depend on time in treatment 
(i.e. quadratic trends could emerge indicating that early- vs late-treatment effects are 
distinct); c) whether the inverse relationships (i.e. outcomes predicting mechanisms) 
are also significant; d) whether patterns of lagged effects are different between MT 
and SMT. In general, we expect that previous week levels in mechanisms will predict 
previous week to current week changes in outcomes, and that the strength of these 
relationships will be strongest from Week 3 to Week 6 (when specific mechanisms 
have improved sufficiently to best affect improvements in outcomes). 
 
10. DATA COLLECTION AND QUALITY ASSURANCE 
10.1 
Data Collection Forms 

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All data will be collected in REDCap; weekly surveys will be done over the phone 
with the RA reading items to subjects and entering their responses directly into 
REDCap or completed online in REDCap directly by the subject. As part of the end 
of the month data check RAs will review the REDCap to ensure that all forms that 
should be marked as completed are and also that no records were erroneously marked 
as completed. 
 
Protocol compliance and data quality review will be ongoing with daily meetings 
between the PIs and research assistants. All data collection will be reviewed within 
days of collection so that the opportunity for feedback to research staff or the 
participants can occur. Additionally, all study materials and data are reviewed for 
accuracy and completeness by a trained research assistant within days of each subject 
completing the study to reduce the possibility of missing data. 
 
The research assistants will be the primary collectors of data, and will refer questions 
to the PIs as they arise. All data entry will be double checked by the PIs, or a separate 
trained research assistant. Participants will complete weekly questionnaires via 
telephone calls with RAs or online via REDCap. Several aspects of the study 
procedures will be designed to minimize risks to confidentiality. Data will be coded 
and transferred to a computer database for later analysis. All paper and computer 
records, will be identified only by subject ID number rather than subject name to help 
ensure confidentiality. All subject records will be maintained in filing cabinets in the 
locked labs of the PIs, and will be accessible only to the PIs and research assistants. 
Hard copies of the data will be maintained for 6 years after the study, after which they 
will be destroyed. Computer data files (without subject IDs) will be maintained by the 
site PIs for future use. Consents and any other forms with identifiable subject 
information will be maintained in a separate locked file from the actual study data 
files, which will be identified only by subject number. All subjects will be informed 
regarding how HIPAA requirements may impact on their study records, and will sign 
a notification regarding this issue. All published data will be reported in a manner in 
which individual data for specific subjects are not identifiable. 
No data will be directly recorded onto a case report form. 
10.2 
Data Management 
We have extensive experience with studies of this type, and plan to employ the same 
types of strategies in the proposed project to address all of these issues. Our intention 
is to use REDCap (developed at Vanderbilt where Co-PI Dr. Bruehl is located) for 
data entry and data storage, a system that it is widely used, highly reliable, and 
secure. Data will be coded on paper and transferred to a computer database for later 
analysis. All paper and computer records, and digital video-recordings of sessions 
will be identified only by subject ID number rather than subject name to help insure 
confidentiality. All subject records will be maintained in filing cabinets in the locked 
offices of the PIs or designees, and will be accessible only to the PIs, co-I’s and 
designees. Hard copies of the data will be maintained for 6 years after the study 
(including the audiotapes/videotapes), after which they will be destroyed. Computer 
data files (without subject IDs) will be maintained by the site PIs for future use. All 

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paper and computer data records will be identified by a subject number assigned 
solely for use in this study rather than by name to help insure confidentiality. The 
individual subjects associated with each subject number will be known only to the 
site PIs and designees. Consents and any other forms with identifiable subject 
information will be maintained in a separate locked file from the actual study data 
files, which will be identified only by subject number. All subjects will be informed 
regarding how HIPAA requirements may impact on their study records, and will sign 
a notification regarding this issue. All published data will be reported in a manner in 
which individual data for specific subjects are not identifiable. 
The issue of “reproducible workflows and practices” is addressed in the originally 
submitted Multi-PI Plan (relevant text follows): "Dr. Burns and Dr. Bruehl will work 
closely to insure that the two study sites develop and implement identical procedures 
and training protocols, and that they acquire data in a coordinated and consistent 
fashion. Both Dr. Burns and Dr. Bruehl will be responsible for managing any 
potential missing data issues, to measure and correct for potential biases, and for 
administrative and fiscal oversight. Regular communication between the PIs via e- 
mail and telephone, as well as regularly scheduled in-person site visits will be used to 
coordinate the study sites. Similar coordination procedures have worked effectively in 
the PIs previous joint NIH-grant funded opioid blockade work (R01-MH071260, 
R01-DA031726, R01-DA037891).” 
10.3 
Quality Assurance 
10.3.1 Training 
The research assistants will be trained and daily supervised by the PIs. The PIs and 
RAs will meet at least weekly to review the week’s activities, protocol violations, 
questions and answers to ensure continued standardized administration of study 
protocol. 
10.3.2 Quality Control Committee 
There is no quality control committee. 
10.3.3 Metrics 
One person enters data, a second checks the data entry and compares to paper record. 
As a double check we will also check frequency and means of data to check for out of 
bound data entry errors. 
10.3.4 Protocol Deviations 
All protocol deviations will be noted in the protocol deviation log and participant’s 
chart. All protocol deviations (minor or major) will be reported to the corresponding 
site IRB through the PIs, and the deviation logs will be uploaded to the shared cloud- 
based document system. It is the policy of the IRB to be notified of any deviation 
from the protocol that results in an increase in risk or a decrease in potential benefit to 
participants. Consistent with IRB policies all minor deviations will be summarized 
and reported to the IRB at the continuing review. Major deviations will be 

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immediately reported to the IRB as specified by IRB procedures along with a 
corrective action plan to ensure that the deviation will not occur again. A “major 
deviation” is defined by the IRB as a deviation that impacts the safety of a subject or 
undermines the integrity of the study. In such a situation, the resulting IRB final 
response will be immediately forwarded to the NCCIH and IMC, along with the 
summary and corrective action plan submitted to the IRB. 
 
A list of protocol deviations will be provided to the Independent Monitoring 
Committee (IMC) each quarter as part of the IMC progress report on January 15, 
April 15, July 15, and October 15. The more detailed semi-annual report will be 
submitted to the IMC on January 15 and July 15, and will include a list and summary 
of any major or minor deviations that occurred. As mentioned above, the IMC report 
prepared every 6 months will be signed by the members of the IMC and will be 
forwarded to the IRBs and NCCIH (reports will be provided more frequently on an 
ongoing basis if concerns are identified). All protocol deviations will be reported to 
NCCIH in the annual progress report and at site visits. 
 
10.3.5 Monitoring 
Protocol compliance and data quality review will be ongoing with daily meetings 
between the PIs and research assistants. All data collection will be reviewed within 
days of collection so that the opportunity for feedback to research staff or the 
participants can occur. Additionally, all study materials and data are reviewed for 
accuracy and completeness by the PI or trained research assistant within days of each 
subject completing the study to reduce the possibility of missing data. 
 
11. PARTICIPANT RIGHTS AND CONFIDENTIALITY 
11.1 
Institutional Review Board (IRB) Review 
This protocol and the informed consent document and any subsequent modifications 
will be reviewed and approved by Rush University Medical Center and Vanderbilt 
University Medical Center IRBs. 
11.2 
Informed Consent Forms 
All individuals agreeing to participate will provide written informed consent during 
Visit 1 (i.e., prior to beginning any study procedures). Subject consent procedures 
will be carried out by individuals designated and trained by each site PI and the IRB 
to carry out these procedures (i.e., the proposed research assistants). In the Consent 
Form, it will be emphasized that subjects may discontinue participating at any time 
and still receive prorated compensation. The recruiter will inform potential subjects 
that participation is completely voluntary, and they may withdraw at any time without 
penalty or running the risk of jeopardizing current and future treatment at the Rush or 
Vanderbilt medical centers. A signed consent form will be obtained from each 
participant. For participants who cannot consent for themselves, such as those with a 
legal guardian (e.g., person with power of attorney), this individual must sign the 

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consent form. The consent form will describe the purpose of the study, the procedures 
to be followed, and the risks and benefits of participation. A copy will be given to 
each participant or legal guardian and this fact will be documented in the participant’s 
record. 
11.3 
Participant Confidentiality 
Several aspects of the study procedures will be designed to minimize risks to 
confidentiality. Data will be coded on paper and transferred to a computer database 
for later analysis. All paper and computer records, and digital video-recordings of 
sessions will be identified only by subject ID number rather than subject name to help 
insure confidentiality. All subject records will be maintained in filing cabinets in the 
locked offices of the PIs or designees, and will be accessible only to the PIs, co-I’s 
and designees. Hard copies of the data will be maintained for 6 years after the study 
(including the videotapes), after which they will be destroyed. Computer data files 
(without subject IDs) will be maintained by the site PIs for future use. All paper and 
computer data records will be identified by a subject number assigned solely for use 
in this study rather than by name to help insure confidentiality. The individual 
subjects associated with each subject number will be known only to the site PIs and 
designees. Consents and any other forms with identifiable subject information will be 
maintained in a separate locked file from the actual study data files, which will be 
identified only by subject number. All subjects will be informed regarding how 
HIPAA requirements may impact on their study records, and will sign a notification 
regarding this issue. All published data will be reported in a manner in which 
individual data for specific subjects are not identifiable. 
11.4 
Study Discontinuation 
The study may be discontinued at any time by the IRB, the NCCIH, the OHRP, the 
FDA, or other government agencies as part of their duties to ensure that research 
participants are protected. 
If the study is discontinued, the PIs will email the IRB consultant assigned to the 
study, the NCCIH program officer, and the IMC to inform them of the 
discontinuation. In addition they will each email their study staff to ensure uniform 
information is disseminated to all. 
 
12. COMMITTEES 
The Independent Monitoring Committee (IMC) will review the following study 
parameters: recruitment status (targeted vs. actual), retention status, enrollment, 
demographics, subject status and adverse events. 
 
13. PUBLICATION OF RESEARCH FINDINGS 
Any presentation, abstract, or manuscript will be made available for review by the 
sponsor and the NCCIH prior to submission. 

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15. SUPPLEMENTS/APPENDICES 
 
 
Appendix I. Side effects from Naloxone compared to Placebo (N = 144) 
 
 
Descriptives - Side Effects on 0-10 Scale (0 = None, 10 = The Most Possible) 
 
 
Descriptive Statistics 
N 
Minimum 
Maximum 
Mean 
Std. Deviation 
nxnausea 
146 
.00 
7.00 
.2808 
.91533 
nxvomit 
144 
.00 
1.00 
.0139 
.11744 
nxdiarrh 
146 
.00 
1.00 
.0137 
.11664 
nxhead 
143 
.00 
5.00 
.3986 
.95046 
nxrestles 
145 
.00 
10.00 
.8207 
1.66111 
nxtrem 
145 
.00 
3.00 
.0828 
.39971 
nxheart 
144 
.00 
3.00 
.1250 
.47120 
nxsweat 
146 
.00 
8.00 
.2671 
1.09097 
nxweak 
143 
.00 
7.00 
.4126 
1.07027 

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nxdrow 
146 
.00 
9.00 
1.6918 
2.09536 
Valid N (listwise) 
143 
 
Note. Prefix nx – naloxone. Side effects means are low. 

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Paired Samples Statistics 
Mean 
N 
Std. Deviation 
Std. Error Mean 
Pair 1 
nxnausea 
.2778 
144 
.91944 
.07662 
plnausea 
.1667 
144 
.52889 
.04407 
Pair 2 
nxvomit 
.0141 
142 
.11826 
.00992 
plvomit 
.0141 
142 
.11826 
.00992 
Pair 3 
nxdiarrh 
.0139 
144 
.11744 
.00979 
pldiarrh 
.0139 
144 
.11744 
.00979 
Pair 4 
nxhead 
.4043 
141 
.95602 
.08051 
plhead 
.3333 
141 
1.05334 
.08871 
Pair 5 
nxrestles 
.8322 
143 
1.66989 
.13964 
plrestles 
.4615 
143 
1.36232 
.11392 
Pair 6 
nxtrem 
.0839 
143 
.40240 
.03365 
pltrem 
.0070 
143 
.08362 
.00699 
Pair 7 
nxheart 
.1268 
142 
.47429 
.03980 
plheart 
.0986 
142 
.45053 
.03781 
Pair 8 
nxsweat 
.2517 
143 
1.07774 
.09013 
plsweat 
.0210 
143 
.14382 
.01203 
Pair 9 
nxweak 
.4113 
141 
1.07618 
.09063 
plweak 
.3050 
141 
1.08195 
.09112 
Pair 10 
nxdrow 
1.7153 
144 
2.10033 
.17503 
pldrow 
1.4236 
144 
2.15997 
.18000 
 
 
Note. Prefix nx = naloxone. Prefix pl = placebo. 

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Paired Samples Test 
Paired Differences 
t 
df 
Sig. (2-tailed) 
Mean 
Std. Deviation 
Std. Error Mean 
95% Confidence Interval of the 
Difference 
Lower 
Upper 
Pair 1 
nxnausea - plnausea 
.11111 
.80306 
.06692 
-.02117 
.24340 
1.660 
143 
.099 
Pair 2 
nxvomit - plvomit 
.00000 
.16843 
.01413 
-.02794 
.02794 
.000 
141 
1.000 
Pair 3 
nxdiarrh - pldiarrh 
.00000 
.11826 
.00986 
-.01948 
.01948 
.000 
143 
1.000 
Pair 4 
nxhead - plhead 
.07092 
1.24008 
.10443 
-.13555 
.27739 
.679 
140 
.498 
Pair 5 
nxrestles - plrestles 
.37063 
1.46161 
.12223 
.12901 
.61225 
3.032 
142 
.003 
Pair 6 
nxtrem - pltrem 
.07692 
.41243 
.03449 
.00874 
.14510 
2.230 
142 
.027 
Pair 7 
nxheart - plheart 
.02817 
.61821 
.05188 
-.07439 
.13073 
.543 
141 
.588 
Pair 8 
nxsweat - plsweat 
.23077 
1.08571 
.09079 
.05129 
.41025 
2.542 
142 
.012 
Pair 9 
nxweak - plweak 
.10638 
1.01209 
.08523 
-.06213 
.27489 
1.248 
140 
.214 
Pair 10 
nxdrow - pldrow 
.29167 
2.14875 
.17906 
-.06229 
.64562 
1.629 
143 
.106 
 
Note. Prefix nx = naloxone. Prefix pl = placebo. Side effect ratings are similar between naloxone and placebo across 7 of 10 
comparisons.