Clinical trial NCT04034004
Conditions: Pain
Keywords: Mindfulness Opioids Pain Naloxone
Sponsor: University of California, San Diego
Start date: 2021-01-01; Completion date: 2022-12-22
Enrollment: 88 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
The purpose of this research study is to see if and how mindfulness meditation affects pain. Specifically, we are interested in assessing if mindfulness is associated with the release of naturally occurring opiates in the body, in response to intravenous (IV) administration of the opioid antagonist naloxone during a chronic low back pain provoking procedure.

Detailed description:
The purpose of this psychophysical and pharmacologic study is to determine if meditation induced pain relief is mediated by endogenous opioids in response to intravenous (IV) administration of the opioid antagonist naloxone during a pain evoking straight leg raise test in response to double-blind intravenous administration (IV) of naloxone/placebo-saline. The aim of this study is to determine if mindfulness-based analgesia is associated with the release of endogenous opioids.

Arms: arm 1: Subjects will participate in four sessions (20 min/session) of mindfulness training. Participants will be taught that perceived sensory events are "momentary" and "fleeting" and require no further evaluation. arm 2: Subjects will participate in four sessions (20 min/session) of mindfulness training. Participants will be taught that perceived sensory events are "momentary" and "fleeting" and require no further evaluation.
Interventions: intervention 1: Mindfulness intervention 2: Naloxone intervention 3: Saline intervention 4: Meditation
Intervention descriptions: intervention 1: A well-validated brief meditation-based mental training regimen \[four sessions; 20 min/session\] is used to teach patients to independently practice closing their eyes and take a deep breath every few minutes. intervention 2: A 0.15 mg/kg bolus dose of naloxone (Naloxone hydrochloride, Amphastar Pharmaceuticals, Inc., Rancho Cucamonga, California) in 25ml normal saline will be administered over 10 minutes. The investigators also will administer a supplementary IV infusion dose of 0.1mg/kg/hour naloxone immediately after bolus infusion will cease till the end of the experiment. intervention 3: A 0.15 mg/kg bolus dose of saline in 25ml normal saline will be administered over 10 minutes. The investigators also will administer a supplementary IV infusion dose of 0.1mg/kg/hour saline immediately after bolus infusion will cease till the end of the experiment. intervention 4: A well-validated brief meditation-based mental training regimen \[four sessions; 20 min/session\] is used to teach patients to independently practice closing their eyes and take a deep breath every few minutes.

Protocol documents:
ICF_002.pdf: 
UCSD Project# 181814 
Submitted 11/26/2019 
University of California, San Diego 
Consent to Act as a Research Subject 
 
Study Title: 
Brain Mechanisms Supporting Chronic Pain Relief by Meditation 
Protocol Number: 
UCSD HRPP Project# 181814 
Sponsor: 
The National Institutes of Health 
Institution: 
UC San Diego Center for Pain Medicine 
Investigator:  
 
Address: 
 
 
Telephone Number: 
Fadel Zeidan, PhD 
 
9452 Medical Center Drive 
La Jolla, CA 92037 
 
858-246-2028 ext.62028 
 
Before you decide whether to participate in this research study, it is important for you to 
understand why the research study is being done and what it will involve.  
 
The decision to participate in this study is up to you. Your participation is completely voluntary. 
Your decision will not affect your relationship with your regular doctor or your current or future 
medical care. 
 
Feel free to discuss this study with your family, friends, and healthcare provider before you make 
your decision whether to participate. Ask about anything you don’t understand or would like 
explained better. Take time to decide whether or not you want to take part in this study. 
 
Who is conducting the study, why you have been asked to participate, how you were selected, 
and what is the approximate number of participants in the study? 
Dr. Fadel Zeidan is conducting a research study to find out more about ways to understand and 
help people with chronic pain. You have been asked to participate in this study because you are 
interested in learning mindfulness and have been diagnosed with chronic low-back pain. Your 
participation is voluntary. There will be approximately 120 participants enrolled at this site. We 
will randomly assigned 40 subjects to each group for the initiation of the final phase of the study.  
 
Why is this study being done? 
The purpose of this study is to see if mindfulness alters brain activation in response to raising 
your leg that may produce the feeling of pain. A technique called functional magnetic resonance 
imaging (fMRI) allows scientists to determine which parts of the brain are active during a 
particular task. This study will provide new information about how mindfulness affects the brain.  
 
What will happen to you in this study and which procedures are standard of care and which 
are experimental? 
If you agree to be in this study, the following will happen to you: 
 
Study Session 1:  You will first report to the UCSD Center for Functional MRI. After signing 
this consent form (if you choose to do so), you will complete our study questionnaires and will 
teach you to use our, what we call, visual analog scales to show us how you feel (about pain, 


 
Page 2 of 8 
 
mood, etc.). We will also administer heat stimuli to your leg that may 
produce the feeling of pain. 
 
Chronic low-back pain inducing procedure: A trained research technician 
will perform the low back pain evoking procedure which is commonly used 
to assess the level of mobility and pain severity you may or may not have. 
This procedure can increase the feeling of pain for 10-15 minutes. In this study session and the 
follow up sessions, we will you test to see if this procedure increases your feeling of pain and 
whether or not you want to participate in our study.  
 
A trained study technician will first instruct you to lie down on your back for 15 seconds and 
then we will ask you if you feel any pain. 
 
We will then see if the angle and height needed for you to increase pain by 2 points on our scale 
and hold the position of your legs with 10 seconds or so. After lowering your legs, we will assess 
your pain ratings again. We will wait until your pain returns to normal before proceeding. After 
completing your questionnaires, you will be dismissed from this session and we will help you 
schedule the follow up sessions. We expect this session to take less than 1.5 hours to complete. 
 
Heat Testing: An electrical device will deliver painful and non-painful thermal stimuli. The 
temperature of the stimulus can range from 35°C to 51°C. This temperature range has been used 
by a number of different laboratories including our own and will not cause any burns.  
 
In all the MRI sessions, heat will be applied to the back of your calf and the back of your 
forearm. We will collect pain ratings, after each thermal pulse and/or after a series of stimuli, 
with the visual analog scale. 
 
Thermal stimulation: As in all of our prior IRB approved experiments (Zeidan, Martucci et al. 
2011, Lobanov, Zeidan et al. 2014, Zeidan, Emerson et al. 2015, Zeidan, Lobanov et al. 2015, 
Zeidan, Adler-Neal et al. 2016, Zeidan, Salomons et al. 2018, Adler-Neal, Emerson et al. 2019, 
Adler-Neal, Waugh et al. 2019), the MEDOC TSA-II will be used to deliver all thermal stimuli. 
All stimulus temperatures will be less than or equal to 50°C, and volunteers will be free to 
escape the stimulator at any time. No stimulus will produce tissue damage. This study will use a 
16x16 mm surface area for the delivery of neutral and noxious stimuli. This modest stimulus area 
allows a relatively wide range of noxious stimuli to be delivered (up to 50°C for 30 seconds) 
without either tissue damage or significant subject withdrawals/drop-outs. Stimuli in this 
temperature range have been used extensively by the PI and numerous laboratories around the 
world and do not produce tissue damage or burns. In order to facilitate removal from the 
stimulator, the stimulator will be attached to a custom-designed thermal stimulation probe 
holder. Participants will place their calf on top of the probe holder and will not be strapped in or 
otherwise restrained. Therefore, participants will be able to simply lift their legs at any time. 
 
Study Session 2: MRI 1:  This session will be conducted at the UCSD Center for Functional 
MRI. You may have the option to attend the interventions via Zoom on an iPad after the first 
session. 
• Functional MRI Sessions 


 
Page 3 of 8 
 
 
The fMRI scans allow us to view the function of your brain. Four hours 
prior to the fMRI scan, you should not smoke, use other tobacco products, 
take any type of medications, and you should not drink coffee or other 
drinks with caffeine. During the MRI scan you will be in a cylindrical 
machine for up to two hours. We will fit you with a belt around your 
chest/belly to measure respiration rate and an oximeter on your index finger to measure heart 
rate. We will then place you inside the scanner.  A special device will hold your head still during 
the scan. Each series of scans takes several minutes and there will be a rest period of a few 
minutes between scans. Before some of the scans, we will ask you to raise your leg that may or 
may not produce the feeling of pain with the assistance of a trained clinician and we will 
subsequently ask you to rate your feeling of pain. We will also place your leg on a custom made 
holder that is attached to the heat stimulating device. You will be able to lift your legs at any 
time. This device will deliver painful and non-painful thermal stimuli. The temperature of the 
stimulus can range from 35°C to 51°C. We will assess your pain ratings (if there are any) after 
each thermal heat stimulation series.  We will scan your brain to determine the brain regions that 
are activated in response to this procedure. You will also receive scans looking at brain structure. 
It is very important for the study for you to be comfortable in the scanner. If you are not 
comfortable, please let us know at any time and we can take you out or try to make you more 
comfortable. The MRI technicians will be only a few feet away and you will be in constant 
communication via an intercom system.  
 
We expect this (and every MRI session) session to take less than 1.5 hours to complete.  
 
After completion of this session, you will be randomized to one of two groups, a mindfulness 
training intervention or a book-listening intervention.  
 
You will be assigned by chance to a study group. Your chance of being assigned to each group is 
1 in 2. Neither you nor the researcher(s) can choose the group to which you will be assigned.  
 
Study Sessions 3-8: Regimen Sessions 1-6:  The following sessions will be held at the UCSD 
Center for Mindfulness. Each of these sessions will take less than 45 minutes to complete. You 
may have the option to attend the interventions via Zoom on an iPad after the first session. 
 
There will be no heat testing during these sessions. 
 
Mindfulness Training: 
Mindfulness training is based on a meditation technique called mindfulness, where we teach you 
how to relax and maintain a focused state of mind. There is no religious or spiritual 
association with this practice. Meditation training will be led by a teacher with extensive 
training and practice in mindfulness meditation. There will be up to a total of twelve meditation-
training sessions. Each session will meet for approximately thirty minutes. In each session, you 
will be asked to close your eyes, relax and to be seated upright in a chair or lay flat on a mat.  
 
Book-Listening Control Regimen:  If you were randomized to this group, you will listen to an 
audio recording of The Natural History and Antiquities of Selborne  in a quiet room across 12 


 
Page 4 of 8 
 
sessions (20mins each session). You will not be allowed to sleep, use 
telephones, or talk to the experimenter during the control sessions.  
 
Study Session 9: Post-Regimen MRI 2: After completing the first six 
sessions of mindfulness training or listening to a book, you will report to the 
MRI Center again.  We perform the exact same procedures described in 
Study Session 2’s MRI session. Yet, if you were randomly assigned to the mindfulness group, 
then you will be asked to practice mindfulness during and after the leg raise test.  
 
Study Sessions 10-15: Regimen Sessions 7-12:  The following sessions will be held at the UCSD 
Center for Mindfulness. Each of these sessions will take less than 45 minutes to complete.  You 
will follow the same procedures as the first six mindfulness or book-listening sessions.  
 
Study Session 16: Post-Regimen MRI 3: We will employ the same study procedures described in 
MRI 2.  
 
How much time will each study procedure take, what is your total time commitment, and how 
long will the study last? 
* The first study session will take about 1.5 hours.  
 
* Each MRI session will generally take approximately one to 1.5 hours of your time.  
 
* Each meditation session will take approximately forty-five minutes. 
 
We will do our best to make the scheduling of the experiment meet your convenience. This study 
should not take more than 6 weeks to complete.  
 
What risks are associated with this study? 
Participation in this study may involve some added risks or discomforts. Possible risks and 
discomforts are detailed below; however, there may be other risks and side effects that are not 
yet known.  
 
1) Straight Leg Raise Test 
The straight leg raise test may produce the feeling of pain. Our goal is to produce a targeted 30% 
increase in the feeling of pain for no more than 20 minutes. Although rare, you may also feel 
discomfort and/or pain for up to 24 hours. We will do all that we can to ensure your comfort 
and/or safety during this procedure. Importantly, you will have complete control of how much 
you raise your leg.  
 
2) MRI 
The MRI scan is not associated with any known risks to your health, but you may be 
uncomfortable because you will be lying in a small space.  If you cannot tolerate this, the scan 
will be stopped immediately. In the MRI scanner, we will provide you with a “squeezeball” that 
you can squeeze which will subsequently end the scan. During scanning, the MRI machine 
produces loud noises, so your ears will be protected by plugs or specialized headphones.  Persons 
with any electronic objects or certain metal objects in their head or body such as cochlear 


 
Page 5 of 8 
 
implants, pacemakers or aneurysm clips may not participate. A checklist of 
excluded metal objects will be presented to you by the MRI technician or 
study staff prior to the MRI scan. There is no radiation associated with this 
type of scan. 
 
3) Reproductive Risks 
Due to unknown risks and potential harm to the unborn fetus, sexually active women of 
childbearing potential must use a reliable method of birth control while participating in this 
study. Reliable methods of birth control are: abstinence (not having sex), oral contraceptives, 
intrauterine device (IUD), birth control injection, tubal ligation, or vasectomy of the partner 
(with confirmed negative sperm counts) in a monogamous relationship (same partner). An 
acceptable, although less reliable, method involves the careful use of condoms and spermicidal 
foam or gel and/or a cervical cap or sponge. We encourage you to discuss this issue further with 
your physicians if you have any questions. 
 
Pregnant women are excluded from participation in this study. Because some methods of birth 
control are not 100% reliable, a urine pregnancy test is required at least 10 days from your last 
normal menstrual period, if you are a sexually active woman of childbearing potential and not 
using reliable birth control. 
 
      4) Randomization  
You will be assigned to a study group at random (by chance). Your assignment is based on 
chance rather than a medical decision made by the researchers. The study group you are assigned 
to might not be the group you would prefer to be in. Your assigned study group might also prove 
to be less effective or have more side effects than the other study groups(s), or other treatments 
available for your condition. 
 
5) Thermal Stimuli 
The purpose of this study is to study pain sensations, so you may feel pain produced by heating 
the skin to temperatures from 35°C (95°F; normal skin temperature) to 49°C (120.2°F). This 
temperature range has been used many times by Dr. Zeidan, the primary investigator (PI) of this 
study, and in many other studies around the world. Your body will not be damaged or burned in 
this study since the heat probe and the temperatures have been carefully chosen to produce the 
necessary sensations safely. This method has been used for many years with no harmful physical 
or psychological (mental) effects.  However, in extremely rare cases, the computer controlled 
stimulator has been reported to malfunction and to cause a burn to the small skin region being 
tested. You will always be awake during the study and free to tell us to turn off the heat probe at 
any time. In addition, you will be able to remove the stimulated body part from the thermal probe 
at any time without any difficulty 
 
Unknown Risks  
There may be side effects that are not yet known. You should call your study doctor if you think 
you are having any of the problems listed above or even if you are having problems that are not 
on this list.  Because this is a research study, there may be some unknown risks that are currently 
unforeseeable. You will be informed of any significant new findings. 
 


 
Page 6 of 8 
 
What are the alternatives to participating in this study? 
You do not have to participate in this study. As this is not a treatment study, 
the only alternative to participating in this study is to not participate.  
 
What benefits can be reasonably expected? 
There may or may not be any direct benefit to you from these procedures. 
The investigator(s), however, may learn more about ways to benefit chronic pain patients in the 
future. 
 
Can you choose to not participate or withdraw from the study without penalty or loss of 
benefits? 
Participation in research is entirely voluntary. You may refuse to participate or withdraw at any 
time without penalty or loss of benefits to which you are entitled. If you decide that you no 
longer wish to continue in this study, you will be requested to talk to the investigators or study 
staff first. You will be told if any important new information is found during the course of this 
study that may affect your wanting to continue. 
 
You will be told if any important new information is found during the course of this study that 
may affect your wanting to continue. 
 
Can you be withdrawn from the study without your consent? 
You may be withdrawn from the study for the following reasons:  
1. Dr. Zeidan believed it was in your best medical interest not to participate. 
2. You had an unexpected reaction. 
3. You failed to follow instructions given to you by the study personnel. 
4. The entire study was cancelled. 
5. If you there are accruing absences and/or tardiness to study sessions. 
 
Will you be compensated for participating in this study? 
In compensation for your time and travel, you will receive up to $500.00 for participating in this 
research. 
 
You will be paid $15.00 for each experimental session (total of 16 sessions = $240.00) that you 
successfully complete and a supplemental $15.00 for each pain testing session (total of 4 pain 
testing session = $60.00) in the laboratory. In the MRI portion of the study, you will receive an 
additional $50.00 for undergoing an MRI scan of brain activation (total MRI payments = 
$150.00).  You will also receive an additional $50 for successfully completing all study sessions. 
 
Are there any costs associated with participating in this study? 
There will be no cost to you for participating in this study. 
 
What if you are injured as a direct result of being in this study? 
If you are injured as a direct result of participation in this research, the University of California 
will provide any medical care you need to treat those injuries. The University will not provide 
any other form of compensation to you if you are injured. You may call the Human Research 


 
Page 7 of 8 
 
Protections Program Office at 858-246-HRPP (858-246-4777) for more 
information about this, to inquire about your rights as a research subject or 
to report research-related problems. 
 
What about your confidentiality? 
Research records will be kept confidential to the extent allowed by law. The 
results of this research study may be presented at scientific or medical meetings or published in 
scientific journals. Your identity and/or your personal health information will not be disclosed 
unless it is authorized by you, required by law, or necessary to protect the safety of yourself or 
others.  There is always some risk that even de-identified information might be re-identified.  
 
Participant information may be provided to Federal and other regulatory agencies as required.  
The Food and Drug Administration (FDA), UCSD Institutional Review Board, and NIH, for 
example, may inspect research records and learn your identity if this study falls within its 
jurisdiction. 
 
If you choose to participate in this study, your medical record at the University of California, San 
Diego will indicate that you are enrolled in a research study. Information about the research and 
any medications or devices you are being given as a participant may also be included in your 
medical record. This part of the medical record will only be available to people who have 
authorized access to your medical record. If you are not a patient at UCSD, a medical record will 
be created for you anyway to ensure that this important information is available to doctors in 
case of an emergency. 
  
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law. This Web site will not include information that can identify you. At most, the Web 
site will include a summary of the results. You can search this Web site at any time. 
 
Who can you call if you have questions? 
Dr. Fadel Zeidan and/or ________________ has explained this study to you and answered your 
questions. If you have other questions or research-related problems, you may reach Dr. Fadel 
Zeidan at 858-246-2028 EXT 62028 
 
You may call the Human Research Protections Program Office at 858-246-HRPP (858-246-
4777) to inquire about your rights as a research subject or to report research-related problems. 
 
Your Signature and Consent 
You agree that you have been given a chance to ask questions about this research study. These 
questions have been answered to your satisfaction. You agree to participate in this study. You do 
not give up any of your legal rights by signing this informed consent form.  
 
You will be given a copy of this signed informed consent form for your own records, as 
well as a signed and dated copy of the Experimental Subject’s Bill of Rights. 
 
You agree to participate. 
 


 
Page 8 of 8 
 
 
 
 
 
 
 
Subject's signature 
 
 
 
 
 
 
Date 
 
________________________                                                              _______________________ 
 

Prot_000.pdf: 
Title: Chronic Low Back Pain and Meditation
NCT Record #: NCT04034004
Date: June 2, 2023
PI: Fadel Zeidan


Biomedical IRB Application Instructions
Page 2
UCSD Human Research Protections Program
New Biomedical Application
RESEARCH PLAN
Instructions for completing the Research Plan are available on the HRPP website.
The headings on this set of instructions correspond to the headings of the Research Plan.
General Instructions: Enter a response for all topic headings.
Enter “Not Applicable” rather than leaving an item blank if the item does not apply to this project.
Version date: 6/02/2023
1.
PROJECT TITLE
The role of endogenous opioids in mindfulness-based chronic pain relief.
2.
PRINCIPAL INVESTIGATOR
Fadel Zeidan, Assistant Professor, Department of Anesthesiology
3.
FACILITIES
* Altman Clinical and Translational Research Institute (ACTRI).
* UCSD Center for Mindfulness (CfM)
4.
ESTIMATED DURATION OF THE STUDY
We estimate that the proposed study will take 5 years to complete. This includes completing data
collection on 60 chronic low back pain patients, data analyses, and time for publication. Each
participant will complete 7 study sessions, which includes review of medical records for confirmation
of chronic low back pain, confirmation of study eligibility (i.e., positive response to the straight leg
raise test, exclusion/inclusion criteria), baseline pain testing, four days of mental training (mindfulness/
non-mindfulness) and two clinical visits where participants will be administered the straight leg raise
test during placebo-saline or naloxone infusion. After all of the data has been collected, the
investigators of the study will be unblinded and statistical analyses will be performed to test the study
hypotheses at which point we will prepare the manuscript for publication.
We do expect recruitment to go smoothly and anticipate that data collection will be completed after 16
months which would provide ample time for data analyses and manuscript preparation.
With respect to the subject focused study procedures, a 4-subject cohort strategy would produce a
start to finish accrual process of 1-2 months or less. An extra 2-3 weeks will be added to the schedule
after one cohort completes to allow for the required accrual of the next group of 8 subjects. The total
outside accrual boundary of this study, taking into account increased stringency with recruitment
towards the end of the study and accounting for a 20% retention loss, is at an estimate of 12 months.
5.
LAY LANGUAGE SUMMARY OR SYNOPSIS (no more than one paragraph)
Chronic pain affects over 100 million Americans and costs the United States an estimated $635 billion
per year in medical expenses and lost work productivity (Institute of Medicine (US) Committee on
Advancing Pain Research 2011, Steglitz 2012). Low back pain is the most common clinical pain
condition (Hoy, Bain et al. 2012) with an average prevalence of 30%; it is the leading cause for
disability (Andersson 1999). In spite of treatment advances, the pervasiveness and burden of chronic
low back pain (cLBP) has dramatically increased Medicare expenditures for steroid injections
( 629%) and opioid treatments ( 423%) (Deyo, Mirza et al. 2009). The widespread use of opioids to
alleviate chronic pain has led to the so-called “opioid epidemic” (Nelson, Juurlink et al. 2015) with an
exponential rise in opioid misuse and addiction (Han, Compton et al. 2015, Saloner and Karthikeyan
2015). These staggering statistics signify the importance of developing fast-acting non-pharmacologic
approaches, such as mindfulness meditation (Jacob 2016), to treat acute exacerbations of cLBP. The
central aim of the proposed NIH sponsored study is to determine if mindfulness-based chronic pain
relief, as compared to non-mindfulness, is associated with the release of endogenous opioids. This
study will examine if mindfulness reduces acutely evoked radicular pain in cLBP through endogenous


Biomedical IRB Application Instructions
Page 3
opioids, as compared to a validated, non-mindfulness technique that we have characterized as non-
mindfulness meditation (Zeidan, Johnson et al. 2010, Zeidan, Emerson et al. 2015). The knowledge
gained from this study will provide novel mechanistic insight to better develop and tailor cognitive
therapeutic interventions to target multiple chronic pain conditions.
6.
SPECIFIC AIMS
Primary Objective
Determine if mindfulness-based chronic back pain relief is mediated by endogenous opioids.
7.
BACKGROUND AND SIGNIFICANCE
Pain is a multidimensional experience that involves sensory, cognitive and affective factors. The
constellation of interactions between these factors renders the treatment of chronic pain challenging
and often a financial burden. In fact, chronic pain affects over 100 million Americans and costs the
United States approximately $635 billion dollars a year. The widespread use of opioids to treat chronic
pain has led to the so-called “opioid epidemic” due to the exponential growth in opioid misuse and
addiction. These staggering statistics highlight the importance of developing, testing and validating
fast-acting, non-pharmacological approaches to treat pain. Mindfulness meditation is a technique that
has been found to significantly reduce pain in experimental and clinical settings. However, lack of
mechanistic data and the assumption that extensive meditation training is required to experience
analgesia has limited the clinical deployment of this cost-effective and narcotic-free treatment. Recent
findings from our laboratory determined that mindfulness meditation reduces pain (mean pain intensity
= 34%; mean pain unpleasantness
= 51%), after only 4 training sessions, through multiple brain
mechanisms (Zeidan, Martucci et al. 2011, Zeidan, Emerson et al. 2015). We have also found that a)
mindfulness-based pain relief is more effective and mechanistically distinct from placebo-analgesia
and b) surprisingly, mindfulness meditation does not engage endogenous opioidergic systems to
reduce pain (Zeidan, Adler-Neal et al. 2016, May, Kosek et al. 2018). Yet, these findings are difficult
to explicitly generalize to chronic pain patients because they were conducted in pain-free individuals
using thermally induced pain. The experience of pain promotes endogenous opioid release in healthy
individuals (Zubieta, Smith et al. 2001, Anderson, Sheth et al. 2002, Bencherif, Fuchs et al. 2002,
Zubieta, Smith et al. 2002). In contrast, there is robust evidence that opioid receptor availability is
significantly reduced in the brain across a wide spectrum of chronic pain conditions (Jones,
Cunningham et al. 1994, Jones, Kitchen et al. 1999, Jones, Watabe et al. 2004, Harris, Clauw et al.
2007, Maarrawi, Peyron et al. 2007, Klega, Eberle et al. 2010, DosSantos, Martikainen et al. 2012,
Brown, Matthews et al. 2015), including chronic low back pain (Bruehl, Chung et al. 2003, Bruehl and
Chung 2006, Bruehl, Chung et al. 2007, Martikainen, Pecina et al. 2013, Bruehl, Burns et al. 2015,
Burns, Bruehl et al. 2017), the cause postulated to be the development of chronic pain (Thompson,
Pitcher et al. 2018). However, while we have repeatedly shown that mindfulness does not employ
endogenous opioids to reduce pain in healthy subjects, it is also possible that the role of endogenous
opioids in mindfulness-based analgesia is more pronounced in clinical pain populations. Thus, the
central aim of the proposed study to determine if mindfulness-based cLBP relief, the most prevalent
and financially burdensome chronic pain condition, is mediated by endogenous opioids.
The use of high dose naloxone is commonplace and routinely employed in mechanistically focused
pain research for over 40 years now (citations selected out of > 1000 studies) (Goldstein and Grevert
1978, Skrabanek 1978, Gracely, Dubner et al. 1983, Posner and Burke 1985, Levine and Gordon
1986, Benedetti 1996, Amanzio and Benedetti 1999, Amanzio, Pollo et al. 2001, Bruehl, Chung et al.
2004, Bruehl, Burns et al. 2008, Burns, Bruehl et al. 2009, Bruehl, Burns et al. 2011, Taylor, Borckardt
et al. 2012, Pereira, Werner et al. 2013, Schoell, Bingel et al. 2013, Dowell, Haegerich et al. 2016,
Springborg, Jensen et al. 2016, Zeidan, Adler-Neal et al. 2016, Berna, Leknes et al. 2018, May,
Kosek et al. 2018) (Grevert, Albert et al. 1983, Amanzio and Benedetti 1999, Benedetti, Arduino et al.
1999) (Adams 1976, Hosobuchi, Adams et al. 1977) (de Andrade, Mhalla et al. 2011, Taylor,
Borckardt et al. 2013) (Mayer, Price et al. 1977) (Stephenson 1978). Naloxone at a high does
provides complete blockade of opioid receptors which allows us to identify the role of endogenous


Biomedical IRB Application Instructions
Page 4
systems in the construction and modulation of pain. If we do not comprehensively block endogenous
opioids, then we will not be able reliably inference our results to the recruitment (or lack thereof) of
endogenous opioids in mindfulness-based pain relief (Grevert, Albert et al. 1983, Spiegel and Albert
1983). Fortunately, naloxone does not produce significant side effects in opioid independent
participants(Mangold, McCaul et al. 2000) and thus we probe the role of endogenous opioids quite
reliably.
This work could guide future clinical trial(s) development to better target outcomes and corresponding
mechanisms supporting meditation-related cLBP relief. If meditation induced chronic pain relief were
associated with non-opioidergic mechanisms, it would provide significant evidence that mindfulness
relieves pain by altering the contextual evaluation of nociceptive information via unique top-down
control processes (Zeidan, Grant et al. 2012). Since opioid and non-opioid mechanisms of analgesia
interact in a synergistic manner, the present work could show that the combination of mindfulness and
pharmacologic/non-pharmacologic analgesic strategies, that rely on opioid signaling, may be acutely
effective in the treatment of clinical pain, a potentially critical finding for the millions of pain patients
seeking a non-opioid therapy.
8.
PROGRESS REPORT
Not applicable. This is a new study.
9.
RESEARCH DESIGN AND METHODS
This proposed NIH-sponsored, randomized, and double-blinded psychophysical and pharmacologic
study includes 7 separate study sessions. In this experiment, we are assessing if mindfulness reduces
acutely evoked radicular pain in cLBP through endogenous opioids as compared to a validated
(Zeidan, Johnson et al. 2010, Zeidan, Emerson et al. 2015), non-mindfulness meditation technique
(non-mindfulness) by administering an opioid antagonist, naloxone, to determine if mindfulness based
cLBP relief is mediated by endogenous opioidergic systems. Importantly, we are employing a well-
validated, non-mindfulness meditation intervention as a placebo control. As previously (Zeidan,
Johnson et al. 2010, Zeidan, Emerson et al. 2015), the non-mindfulness group will be instructed that
they are in the “mindfulness meditation” intervention. Thus, we must blind non-mindfulness subjects to
the nature of their respective intervention.
Each study session will be conducted on a separate day. All potential participants will be assessed for
study eligibility at the pre-study screening and first study session. Participants will have 40 days to
complete the study.
Exemption from 21 CFR 312.2(b)(iii): We and many other groups are exempt from key criterion
outlined in 21 CFR 312.2(b)(iii) (The investigation does not involve a route of administration or dosage
level or use in a patient population or other factor that significantly increases the risks (or decreases
the acceptability of the risks) associated with the use of the drug product) because the dosage
employed has been repeatedly demonstrated to be highly safe and effective at examining the study
aims. This is demonstrated below and described in the attached IND Exempt supplement document
(item 25).
Critically, the use of high dose naloxone is commonplace and routinely employed in mechanistically
focused pain research for over 40 years now (citations selected out of > 1000 studies) (Goldstein and
Grevert 1978, Skrabanek 1978, Gracely, Dubner et al. 1983, Posner and Burke 1985, Levine and
Gordon 1986, Benedetti 1996, Amanzio and Benedetti 1999, Amanzio, Pollo et al. 2001, Bruehl,
Chung et al. 2004, Bruehl, Burns et al. 2008, Burns, Bruehl et al. 2009, Bruehl, Burns et al. 2011,
Taylor, Borckardt et al. 2012, Pereira, Werner et al. 2013, Schoell, Bingel et al. 2013, Dowell,
Haegerich et al. 2016, Springborg, Jensen et al. 2016, Zeidan, Adler-Neal et al. 2016, Berna, Leknes
et al. 2018, May, Kosek et al. 2018) (Grevert, Albert et al. 1983, Amanzio and Benedetti 1999,
Benedetti, Arduino et al. 1999) (Adams 1976, Hosobuchi, Adams et al. 1977) (de Andrade, Mhalla et
al. 2011, Taylor, Borckardt et al. 2013) (Mayer, Price et al. 1977) (Stephenson 1978).


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In addition, our laboratory has now successfully completed three separate experiments combining
noxious stimulation, mindfulness-based meditation (and sham-mindfulness), and IV naloxone/saline
infusion employing the exact procedures that match this NIH sponsored project.
In our first two published studies (Zeidan, Adler-Neal et al. 2016, May, Kosek et al. 2018), we
employed the exact naloxone dosages and procedures (very safely) as the ones for this study.
We have recently completed (data collection completed; writing manuscript now) a third study, where
we employed what we (and the NIH) characterized as a cross-over design, naloxone infusion
procedure in 60 individuals without any safety events. The four participants that exhibited side effects
in our Journal of Neuroscience, 2016 study was related to these subjects’ previous history of syncope,
fear of needles, and blood and not directly related to naloxone. Thus, in our latest study (in
preparation), we excluded individuals that have no prior history of syncope, fear of blood/needles, and
report no side effects, safety and/or adverse events.
Further, the naloxone dosages employed in our laboratory studies corresponded to a 0.15 mg/kg
bolus dose of naloxone (Naloxone HCI, Amphastar Pharmaceuticals, Inc., Rancho Cucamonga,
California) or saline in 25ml normal saline was administered over 10 minutes via the intravenous (IV)
line inserted into the antecubital vein of the non-dominant arm. To ensure that naloxone antagonizes
opioid receptors for entirety of the experiment, we administered a supplementary IV infusion dose of
0.1mg/kg/hour naloxone or saline immediately after bolus infusion ceased till the end of the
experiment. This large dose comprehensively antagonizes endogenous opioids (Levine and Gordon
1986) and reverses pain relief produced by placebo (Levine, Gordon et al. 1978, Grevert, Albert et al.
1983, Amanzio and Benedetti 1999, Benedetti, Arduino et al. 1999), electrical stimulation of
periventricular gray matter (Adams 1976, Hosobuchi, Adams et al. 1977), transcranial magnetic
stimulation (de Andrade, Mhalla et al. 2011, Taylor, Borckardt et al. 2013), acupuncture (Mayer, Price
et al. 1977), and hypnosis (Stephenson 1978).
In our third study conducted at the University of Oregon, we used an even larger dosage of 0.15
mg/kg bolus dose of naloxone (Naloxone HCI, Amphastar Pharmaceuticals, Inc., Rancho
Cucamonga, California) with a .20 mg/kg/hour infusion. There were no side effects exhibited in this
study. Further, other groups (Mangold, McCaul et al. 2000, Eippert, Bingel et al. 2009, Schoell, Bingel
et al. 2013, Berna, Leknes et al. 2018) have employed larger IV dosages of naloxone than our
protocol without any side effects or adverse events. We have extensively piloted our procedures to
ensure that no side effects arise, we do not unblind subjects and can comprehensively block
endogenous opioids. We have run over 180 participants with only four minor side effects in a study
where we did not exclude subjects with prior history of syncope, fear of blood and/or needles. We will
employ this new exclusion criteria in the present study.
Duration of Human Involvement
Successful completion of the proposed study will include a total of 7 sessions. Prior to their enrollment
potential subjects will first be screened over the phone to determine if they qualify for the proposed
project. There may be up to 2 weeks between a patient’s initial screening and their official enrollment
of the study.
We will provide up to a 14-day gap between enrollment and the first experimental session to provide
time to enroll cohorts, group randomization, and individualized scheduling. Once the schedules have
been determined, the participants’ baseline assessment and baseline testing session will be
scheduled, and coordinator study team member will schedule intervention regimens. Study
participants will be required to complete 4 respective training sessions over a 14-day period (including
weekends; interventions will be offered over the weekend). This approach will increase study
feasibility, compliance and adherence. The clinical pharmacologic testing sessions will be scheduled


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individually during the respective interventions. After the first pharmacologic testing session,
participants must wait no less than 2 days and no more than 6 days to complete the second clinical
pharmacologic testing session.
Planned Data Collection
Data Collection:
The following information will be collected from all patients: name, date of birth, age, gender, ethnicity,
telephone number email address, medical record number (will be deleted from study file once review
of medical records is complete), diagnosis, condition, current/previous drug regimen, handedness and
meditation experience. Also, in order to process subject compensation, address and social security
number will be collected.
Experimental Sessions: All of the proposed procedures are characterized as “experimental”.
Session 1 Pre-Regimen Session: Subjects will first report to the Altman Clinical and Translational
Research Institute (ACTRI).
This session will also be employed to determine participant eligibility based on our inclusion and
exclusion criteria and will serve as the baseline behavioral control. After obtaining informed consent,
subjects will complete study questionnaires (see Questionnaires) and will be trained to reliably use the
visual analog scale (VAS) to rate their pain (Zeidan, Martucci et al. 2011, Zeidan, Emerson et al.
2015, Zeidan, Lobanov et al. 2015), in response to heat stimuli (32 stimuli of 5 second duration)
ranging from 35-49°C in a fixed order, and the chronic low back pain exacerbation procedure. This
psychophysical training will also maximize reproducibility of pain ratings (Rosier, Iadarola et al. 2002).
These assessments will be based on self-report, review of medical history from the subject’s
current/previous physician(s), and/or confirmation of chronic low back pain diagnosis by a study
physician during Session 1 at the ACTRI. In the review of a subject’s medical history, a trained study
staff member will review and record necessary data, in order to confirm eligibility criteria are met.
Information will be reviewed from the EPIC medical records of subjects who are UCSD patients or
from copies of the medical records provided by non-UCSD patient subjects. These outcomes include:
the subject’s diagnosis (spinal pathology and date), condition, and current/previous drug regimen.
Confirmation of chronic low back pain must also be determined through performance of the straight
leg raise test. That is, a study physician (Krishnan Chakravarthy) or trained research technicians will
confirm diagnosis by examining the medical history record. If a medical record is not available, then
we will confirm low back pain by determining if the patient is “positive” on the straight leg raise test,
which will serve as the primary method of low back pain confirmation. As described in Session 1, we
will test to see if the straight leg raise test (SLR) produces an increase in subjective pain
corresponding to the low back. Subjects that report an increase of pain when lifting their legs up from
15-60 degrees, or to a height in that range, will be characterized as “straight leg raise test positive.”
This is an indicator of radicular pain stemming from the low back.
Psychophysical Testing
Thermal stimulation: As in all of our prior IRB approved experiments (Zeidan, Martucci et al. 2011,
Lobanov, Zeidan et al. 2014, Zeidan, Emerson et al. 2015, Zeidan, Lobanov et al. 2015, Zeidan,
Adler-Neal et al. 2016, Zeidan, Salomons et al. 2018, Adler-Neal, Emerson et al. 2019, Adler-Neal,
Waugh et al. 2019), the MEDOC TSA-II will be used to deliver all thermal stimuli. All stimulus
temperatures will be less than or equal to 50°C, and volunteers will be free to escape the stimulator at
any time. No stimulus will produce tissue damage. This study will use a 16x16 mm surface area for
the delivery of neutral and noxious stimuli. This modest stimulus area allows a relatively wide range of
noxious stimuli to be delivered (up to 50°C for 30 seconds) without either tissue damage or significant
subject withdrawals/drop-outs. Stimuli in this temperature range have been used extensively by the PI


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and numerous laboratories around the world and do not produce tissue damage or burns. In order to
facilitate escape from the stimulator, the stimulator will be attached to a custom-designed thermal
stimulation probe holder. Participants will place their calf on top of the probe holder and will not be
strapped in or otherwise restrained. Therefore, participants will be able to simply lift their legs at any
time.
Chronic low-back pain exacerbation procedure: Co-investigators and/or trained study staff will conduct
the cLBP exacerbating straight leg-raise test, which is commonly used to assess mobility and pain
severity in those with low-back pain (Mens, Vleeming et al. 1999, Roussel, Nĳs et al. 2007, Kwong,
Virani et al. 2013, Bruno, Millar et al. 2014). This procedure significantly increases behavioral and
neural pain responses for 10-15 minutes (Apkarian, Krauss et al. 2001, Sharma, Gupta et al. 2011,
Wasan, Loggia et al. 2011, Loggia, Kim et al. 2013). Session 1 will determine if the straight leg raise
test will reliably exacerbate cLBP and allow patients to decide if they are willing to perform
subsequent straight leg raises. Co-investigators and/or trained staff will first instruct patients to lie in
supine position for 15 seconds before collecting baseline pain ratings. For each patient, we will first
measure the straight leg angle/height required to produce a 2-point VAS pain intensity increase using
a goniometer [70]. With the aid of study staff, participants will again perform a straight leg-raise
ranging from 15-60° (Rebain, Baxter et al. 2002, Summers, Malhan et al. 2005), depending on the
angle/height required to produce the targeted pain increase and hold the position for 10 seconds.
After lowering their legs, we will assess if the patient’s pain ratings increased to the targeted pain
increase compared to baseline pain ratings (Wasan, Loggia et al. 2011). This procedure will be
repeated up to three times to ensure inter-maneuver reliability (Wasan, Loggia et al. 2011). Since this
procedure can exacerbate pain for up to 15 minutes, we will wait at least 20 minutes between tests to
confirm that pain returned to baseline. The leg-raise angle/height corresponding to a 2-point VAS pain
increase will be targeted in each subsequent testing session. This session should take approximately
2.0 hours or less to complete.
Procedures
Pre Rest + Heat: A thermal probe will be placed on the back of the “unaffected” calf (i.e., non-
responsive to SLR) while patients lie in the supine position. They will be instructed to “rest with your
eyes closed” for 5 minutes. We will administer the so-called “Heat” series that includes 10 alternating,
12-second plateaus of noxious (49°C) and 35°C stimulation. VAS pain intensity, VAS unpleasantness,
and numerical pain ratings will be collected after the series has completed. We will then remove the
calf from the probe holder.
Pre Rest + SLR: After identifying the appropriate angle/height to induce a 2-point pain increase,
patients will lie in the supine position and will be instructed to “rest with your eyes closed” for 5
minutes. VAS pain ratings will then be collected. With the aid of a technician, patients will then lift their
legs to the angle/height calibrated to produce a 2-point VAS pain increase. After 5 minutes, we will
collect pain ratings.
Post Rest + SLR: We will wait 10 minutes before continuing the study to control for the time spent
administrating the drug/saline bolus take effect. VAS pain ratings will be collected after 10 minutes.
We will then match the procedures employed in Pre-Rest + SLR.
Post Rest + Heat: A thermal probe will be placed on the back of the “unaffected” calf while patients lie
in the supine position. They will be instructed to “rest with your eyes closed” for 8 minutes. We will
then match the procedures employed in Pre Rest + Heat.
Patient Randomization:
After successful completion of session 1, participants will be randomized to their respective group.
Randomization will be tracked in the Screening/Enrollment Log that is maintained by the clinical


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coordinator. Randomization will be stratified so that each sex will have their respective list of
randomization codes. Males and females will be randomized without replacement across a block of 60
codes using an Excel-based random number generator. Male and female participants will be
randomized within three days of their respective scheduled psychophysical training session. The two
treatment arms (mindfulness meditation = A; non-mindfulness meditation =B) will be permuted with
respect to treatment assignment, in a double-blind fashion, respectively. We will employ a similar
randomization procedure within each group to determine when (i.e., Session 6 or 7) each participant
will receive naloxone and saline in a crossover manner.
Sessions 2-5: Regimen:
Procedures corresponding to the regimen sessions will parallel the mindfulness meditation and non-
mindfulness meditation training regimens employed previously (Zeidan, Emerson et al. 2015).
Interventions will be conducted in groups of one (1 = makeup sessions) to six (Zeidan, Gordon et al.
2010, Zeidan, Johnson et al. 2010, Zeidan, Johnson et al. 2010, Zeidan, Martucci et al. 2011, Zeidan,
Martucci et al. 2014, Zeidan, Emerson et al. 2015) and taught by certified facilitators at the UCSD
Center for Mindfulness (CfM). A research technician will greet patients as they arrive to the CfM and
guide them to their respective classrooms. Both prior to and after completion of each intervention
regimen, the research technician will issue and collect study assessment data (SAI both pre and post-
intervention session; Perceived Intervention Effectiveness post-intervention session) to each
participant. Each of these sessions will take no longer than 45 minutes to complete.
Mindfulness Meditation Training: We will use our well-validated mindfulness-based mental training
regimen to teach participants to independently practice mindfulness meditation (Zeidan, Johnson et
al. 2010, Zeidan, Johnson et al. 2010, Zeidan, Martucci et al. 2011, Zeidan, Emerson et al. 2015,
Zeidan, Adler-Neal et al. 2016). In each of the four 20-minute sessions, participants will be asked to
close their eyes, focus on the breath sensations, recognize distracting thoughts and feelings, and to
“simply let go” of sensory events without judgment. They will be taught that perceived sensory and
affective events are “momentary” and “fleeting” and do not require evaluation.
Non-mindfulness Meditation Training: The main purpose of the non-mindfulness meditation regimen is
to serve as an active control for a crucial, essential element of mindfulness meditation (i.e., mindful
attention to breath and non-reactivity to sensory events)(Zeidan, Johnson et al. 2010, Zeidan,
Emerson et al. 2015). This regimen is designed so that the primary difference between the
mindfulness and non-mindfulness meditation training is the mindfulness meditation group’s explicit
mindfulness-based instructions (e.g., mindful attention to the breath). The non-mindfulness meditation
group will be told that they are randomly assigned to the meditation group (Zeidan, Johnson et al.
2010, Zeidan, Emerson et al. 2015). In each of the four 20-minute training sessions, participants will
be instructed to close their eyes, and to take a deep breath “as we sit here in meditation” every 2-3
minutes (Zeidan, Johnson et al. 2010, Zeidan, Emerson et al. 2015). All other aspects (training room,
posture, facilitator, time providing instruction) of the non-mindfulness meditation intervention will be
matched.
Sessions 6 & 7: Post-Regimen Session: We will employ a double-blinded crossover design to
correspond to the administration of the opioid antagonist, naloxone and placebo-saline across two
separate sessions at UCSD’s Altman Clinical and Translational Research Institute (ACTRI). A total of
30 subjects in each group will receive naloxone in Session 6 and saline in Session 7. Conversely, the
other 30 subjects in each group will receive saline in Session 6 and naloxone in Session 7. After
successful completion of their respective regimen, participants will report to the ACTRI. A research
technician will greet patients as they arrive to the ACTRI and guide them to the clinic room. Next, the
research technician will issue study assessments to the participant. ACTRI nurses will then administer
an opiate-focused urine drug screening to confirm that no participants are using opioids to remove the
risk of opioid withdrawal symptoms during naloxone administration, and a pregnancy test (if
applicable). Weight will be subsequently measured to confirm the prescribed drug dosage. Next, the


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research technician will issue study assessments to the subject. We will recalibrate each participant’s
leg raise height/angle required to elicit a 2-point pain increase employing the methods described in
Session 1. An ACTRI nurse will then insert the IV catheter into
the non-dominant arm of each participant. As previously employed (Zeidan, Adler-Neal et al. 2016) for
safety purposes, blood pressure, respiration, oxygen saturation, and heart rate will be systematically
monitored/recorded. These sessions should take approximately 1.0 hour to complete.
Pre Rest + Heat: A thermal probe will be placed on the back of the “unaffected” calf while patients lie
in the supine position. They will be instructed to “rest with your eyes closed” (~ 5 minutes). We will
administer a “Heat” series that includes 10 alternating, 12-second plateaus of noxious (49°C) and
35°C stimulation. After completion, we will collect pain ratings.
Pre Rest + SLR: The procedures employed in Pre Rest + SLR will be matched to those employed in
Session 1. Briefly, patients will lie in the supine position and be instructed to “rest with your eyes
closed”. VAS pain ratings will then be collected. With the aid of a technician, participants will then lift
their legs to the angle/height calibrated to produce a 2-point VAS pain increase. After completion, we
will collect pain ratings.
Bolus: An ACTRI nurse will then initiate the naloxone/saline bolus (based on weight) for approximately
8 minutes.
Pre Meditation + SLR: After completion of the bolus (~8 minutes), a study technician will aid
participants to lift their legs to the height/angle calibrated to produce a 2-point VAS pain increase.
Participants in the mindfulness and non-mindfulness meditation groups will then be instructed to
“begin meditating until the end of the session” (Zeidan, Martucci et al. 2011, Zeidan, Emerson et al.
2015). An ACTRI nurse will then initiate the naloxone or placebo-saline infusion. After completion, we
will collect pain ratings.
Post Meditation + Heat: A thermal probe will be placed on the back of the “unaffected” calf while
patients lie in the supine position and during meditation. We will administer a “Heat” series that
includes 10 alternating, 12-second plateaus of noxious (49°C) and 35°C stimulation. After completion,
we will collect pain ratings.
Patients will return to the ACTRI to complete session 7 and will follow the same procedures (except
for drug administration) as Session 6. Participants must wait 2 days to participate but no longer than 7
days to complete Session 7. Drug symptomology will be assessed after each session.
Primary Outcome Measure(s):
1.
Visual Analog Scale (VAS) and numerical rating scales (NRS): Pain ratings (VAS pain
intensity, VAS unpleasantness, and numerical pain ratings) will be assessed in response to
the straight leg raise test.
2.
exploratory outcomes include those corresponding to “heat induced pain ratings” (i.e.
thermal stimulation), and lying supine. The minimum rating ("0") is designated as "no pain"
whereas the maximum ("10") is labeled as "most intense imaginable" or "most unpleasant
imaginable.” Higher numbers correspond to higher pain.
a.
We will collect naloxone and saline induced changes in pain intensity and pain
unpleasantness ratings
Sample Size Determination: Our targeted sample size is 60 cLBP patients (30/group). To conduct
group comparisons among the two primary outcomes (naloxone + saline induced changes in pain
intensity + unpleasantness) and to ensure an overall type I error rate < 0.05, we used conservative
Bonferroni corrections (p = .025) in all power calculations. Employing the pilot data corresponding to
our previous work (Wells et al., 2020), we fit repeated measures ANOVA models that include indicator


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variables for group (mindfulness vs. sham) and drug (naloxone vs. saline). The estimated square root
of mean square errors is 0.23 (23%) and 0.30 (30%) for pain intensity and pain unpleasantness,
respectively. Thirty subjects will provide 80% power to detect a pain rating difference of 22% between
the naloxone and saline conditions in the non-mindfulness group with an estimated SD of 0.3 (30%).
We expect no meaningful differences in pain reductions between naloxone and saline infusion during
mindfulness meditation. Thus, we will have 80% power to detect a significant group X drug type
interaction. Finally, 30 subjects/group will provide 80% power to detect a significant group difference
of 19% for pain intensity and 24% for pain unpleasantness. Such effect sizes parallel those observed
in our pilot data(Wells et al., 2020). Statistical power will be also greater when pre-regimen pain
ratings are entered as covariates to reduce residual variance.
Questionnaires for Study Assessments:
All questionnaires will be delivered using Research Electronic Data Capture (REDCap) on iPad
tablets administered and supervised by study personnel. After a number of pilot trials in our
laboratory, the total amount of time to complete all assessments averaged 30 minutes with a range of
25-45 minutes. The questionnaires to be presented on the REDCap platform include the following:
2.
Five Facet Mindfulness Questionnaire (FFMQ): This is a 39-item multidimensional measure of
trait mindfulness and includes five subscales: non-reactivity, nonjudgement, describing, observing,
and acting with awareness.
3.
Profile of Mood States Questionnaire (POMS-short form): This is a 40-item measure of 6 mood
states: tension-anxiety, depression-dejection, anger-hostility, vigor-activity, fatigue-inertia, and
confusion-bewilderment. This assessment is recommended by the IMMPACT group as a core
measure of emotional functioning.
4.
Subjects’ Global Impression of Change (PGIC): This is a self-report assessment
recommended to evaluate self-reported perception of improvement over trial/efficacy of treatment.
5.
Pain Self Efficacy Questionnaire (PSEQ): This is a 10-item questionnaire that’s designed to
assess confidence in performing activities while in pain, for those with ongoing pain.
6.
PROMIS 29-Item Profile: This is a 29-item generic health-related survey that assesses the
following 7 domains: depression, anxiety, physical function, pain interference, fatigue, sleep
disturbance, and ability to participant in social roles/activities.
7.
PROMIS Pain Behavior Measure: This is a 5-item questionnaire that measures complaints of
suffering, verbal or nonverbal (i.e. such as when I am in pain I squirm), from the past 7 days.
8.
PROMIS Physical Function Measure: This is a 13-item self-report assessment that measures
capability rather than actual performance of physical activities.
9.
PROMIS Pain Quality Measure: This is a 5-item questionnaire that measures sensory quality
of pain experience (throbbing, aching, etc).
10.
Chronic Pain Acceptance Questionnaire (CPAQ-R): This is a 20-item assessment designed to
measure acceptance of pain. The acceptance of chronic pain is thought to reduce attempts to avoid or
control pain and thus focus on engaging in valued activities.
11.
State Anxiety Inventory (SAI): The SAI is a prominent 20-item measure for anxiety, and will be
utilized as a manipulation check for our behavioral interventions.
12.
Brief Pain Inventory (BPI): This is an 8-item assessment widely used to measure clinical pain.
13.
SF-12 Health Survey (SF-12): This is a 12-item version of the SF-36 item Health Survey
designed to assess general mental and physical functioning, and overall health-related quality of life.
14.
Pain Catastrophizing Scale (PCS): This is a 13-item assessment derived from definitions of
catastrophizing. The PCS yields a total score and three subscale scores assessing rumination,
magnification, and helplessness in subjects.
15.
Beck Depression Inventory (BDI): This is a 21-item standard assessment widely used to
measure clinical depression.
16.
The Freiburg Mindfulness Inventory (FMI): This is a 14-item standard mindfulness scale to
measure potential changes in mindfulness before and after intervention.


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17.
Roland-Morris Disability Questionnaire (RMDQ): This is a critical assessment for the chronic
low back pain phenotype and was recommended for use by the NIH.
18.
Pittsburgh Sleep Quality Index (PSQI): This is a 10-item assessment designed to measure
quality of sleep.
19.
Cohen Perceived Stress Scale (PSS): This assessment is critical for controlling stress in our
analyses as well as a potential predictor in clinical pain improvements
20.
Multidimensional Assessment of Interoceptive Awareness (MAIA): This is a 32-item
multidimensional instrument that includes 8 scales ranging from 3 to 7 items each. The scales are
noticing, not-distracting, not-worrying, attention regulation, emotional awareness, self-regulation, body
listening, and trusting.
21.
Nondual Awareness Dimensional Assessment (NADA): This is a 13-item standardized
instrument capable of facilitating quantitative investigation of nondual awareness using two
dimensions: bliss and self-transcendence.
22.
Social Connectedness Scale (SCS): This is a 20-item assessment designed to measure social
connectedness, an attribute of the self that reflects cognitions of enduring interpersonal closeness
with the social world.
Drug Administration: All studies will be conducted with the supervision of ACTRI nurses in the ACTRI.
As previously conducted (Zeidan, Adler-Neal et al. 2016), a 0.15mg/kg bolus dose of naloxone
(Naloxone HCI, Amphastar Pharmaceuticals) or 25ml of normal saline will be administered over 10
minutes via the IV line of the antecubital vein of the non-dominant arm. Onset of naloxone-induced
opioidergic antagonism occurs within 2 min of infusion and exhibits an average half-life of 64 min
(Ngai, Berkowitz et al. 1976). To further ensure that naloxone will antagonize opioid receptors for the
study entirety, we will administer a supplementary maintenance intravenous infusion dose of 0.15
mg/kg/h naloxone or saline immediately after bolus infusion ceases. The duration of the study from
the onset of IV infusion to completion will be no more than 25 (average time of infusion = approx. 15
minutes). Only the study physicians, research pharmacist, and study coordinator will be aware of
participant drug assignment.
Sample Size Determination & Power:
Assuming a conservative 20% dropout rate, we will recruit and randomize a total of 74 cLBP patients
(n=37/group) to a mindfulness meditation or non-mindfulness meditation regimen. To conduct group
comparisons among the two primary outcomes (naloxone + saline induced changes in pain intensity +
unpleasantness) and to ensure an overall type I error rate < 0.05, we used conservative Bonferroni
corrections (p= .025) in all power calculations. Employing the pilot data corresponding to preliminary
findings and our previous work [22], we fit repeated measures ANOVA models that include indicator
variables for group (mindfulness vs. non-mindfulness), drug (naloxone vs. saline), and session order.
The estimated square root of mean square errors is 0.23 and 0.30 for pain intensity and pain
unpleasantness, respectively. Thirty participants per group will provide 80% power to detect a group
difference of 0.19 for pain intensity and 0.24 for pain unpleasantness. Such effect sizes are consistent
with those observed from our pilot data. Statistical power will be also greater when pre-regimen pain
ratings are entered as covariates to reduce residual variance.
Data Analyses and Interpretation:
Primary Outcome: Age and sex will be entered as covariates in all appropriate analyses if between
group differences exist. To test study hypotheses, a 2 (group) X 2 (rest vs. manipulation) X 3
(naloxone vs. saline) repeated measures (RM) ANOVA will be employed. Post-hoc paired samples t-
tests (in each group) will be conducted to test the hypotheses that non-mindfulness meditation but not
mindfulness induced analgesia will be reversed by administration of naloxone but not saline.
Exploratory analyses may be conducted (in supplementary papers) on the psychological assessments
(Questionnaires for Study Assessments) to better appreciate the relationship in dispositional pain and
the potential changes in pain responses due to the respective interventions.


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Inclusion of Women and Minorities: Participants will include all sexes and races. We plan to screen
from over 2500 cLBP patients from the ACTRI’s pain recruitment service, 11 separate providers, and
the local community. Based on the latest San Diego-based demographic consensus, we plan to
recruit 60% White, 16% Asian, 7% Black, 0.5% Native American, 0.5% Pacific Islander, 12% Other
race, 5% two or more races (We expect that 29% of our participants will be Hispanic or Latino). If
necessary to obtain minority representation, under-represented racial groups will be targeted
specifically for recruitment.
General Considerations:
Data for all individual participants randomized or exposed to study drug will be presented in data
listings. Continuous data will be summarized using the following descriptive summary statistics: the
number of subjects (n), mean, SD, SE, median, minimum value (min), and maximum value (max).
Categorical data will be summarized using counts and percentages.
10.
HUMAN SUBJECTS
Total number of subjects to be enrolled at UCSD
Our targeted sample size is 60 cLBP (30/group). We have exhibited a relatively low attrition rate on
previous work, thus we request permission to enroll 74 participants with the goal of retaining 60
participants.
Age: Age will range between 18 and 65 years.
Sex: We will have equal males and females in each group. Groups will be matched by age and sex
(15 males/15 females).
Ethnic background: We will include all ethnicities.
Health status: Participants must have a chronic low back pain diagnosis.
All study participants will be recruited from the ACTRI and the local community. We will employ our
NIH-approved exclusion and inclusion criteria delineated in previous studies examining cLBP [27; 37;
42] as described below.
Eligibility Criteria: Patients will qualify for the study if medical evaluation demonstrates chronic low
back pain that is evoked by lifting the legs. Existing medical records, per physician discretion and low
back examinations will confirm diagnosis. Study physicians will confirm diagnosis (Fardon 2001,
Wasan, Davar et al. 2005, Jamison, Ross et al. 2010, Wasan, Loggia et al. 2011, Fardon, Williams et
al. 2014).
Inclusion criteria include those who:
a)
are between 18-65 years old;
b)
have ongoing chronic pain (pain intensity ≥3 on a 0-10 VAS);
c)
have radicular pain for at least 3 months;
d)
are not using other pain management procedures (i.e. CBD oil products) during the study
period;
e)
are not taking opioids;
f)
if female and of a child bearing potential age, are not pregnant or nursing mothers;
g)
have not had back surgery within a year of the study start date;
h)
lack sensory/motor deficits that preclude participation in pain-inducing procedures;
i)
have no meditation experience;
j)
are straight leg raise test positive
k)
do not have any known allergies to naloxone or similar drugs


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l)
do not have a history of syncope and/or fear of needles/blood.
11.
RECRUITMENT AND PROCEDURES PREPARATORY TO RESEARCH
Patients will be recruited through two primary streams: (1) from IRB approved flyers and
recommendations by UCSD study physicians and 2) the ResearchMatch website. We will begin study
recruitment after we have completed all NIH oversight requirements.
To be clear: we will post IRB approved flyers throughout the community and UCSD Pain Medicine
physician offices. If a physician believes a patient is qualified for this study, they will refer the potential
participant to the flyer at which point they can voluntarily call the coordinator to assess eligibility. We
will not access medical records until after we have permission and the subject completes Visit 1’s
procedures.
Recruitment Stream 1:
The study will be advertised on ResearchMatch to gain interest for participation in the pilot to this
cLBP study. This site will allow for members of the community to inquire as to their potential interests
in the study’s goals and requirements.
Recruitment Stream 2:
In addition, we will both advertise with flyers within these clinics that see thousands of patients each
year. Hence, the sheer aggregate of potential community and clinical sources for this study would
suggest more than adequate potential for our recruitment aims. The patient’s treating physician will be
requested to approach the participant and introduce the study. The treating physician will further
discuss the research study with the potential participant and refer them to the coordinator’s contact
information at which point the patient has the discretion to contact the study coordinator. There will be
no direct contact of the potential research participant by the study staff unless prompted by the
potential participant. Their treating physicians can refer them to our study and they will call us, if they
choose, on their volition.
If a potential participant is interested in the study. They will email and/or call the study coordinator to
assess eligibility. This is strictly based on the patients’ discretion and volition. A brief subset of
preliminary eligibility criteria (such as age, gender, etc.), will be reviewed by study personnel to
determine subjects’ preliminary eligibility for the research study during the phone screening and Visit
1.
The phone screen script will be employed to identify preliminary study eligibility. The study team
member screening potential participants, will obtain verbal consent before any participant information
is collected, see item 12 below for request for waiver of documented consent for this screening.
Subjects who fulfill the preliminary eligibility criteria will be offered further participation in this study.
Preliminary eligibility may be determined at the time of phone screening, but formal eligibility will only
be determined after informed consent is obtained and a standard, stand-alone HIPAA authorization
form is signed. The primary method of determining eligibility for the study is the straight leg raise test
confirmation during Visit 1. Standard HIPAA authorization to collect research data from the patient’s
medical record will be obtained at the time of informed consent during Session 1. Only subjects who
have consented and provided HIPAA authorization will have identifiers or linked information (e.g.,
subjects initials, study numbers, etc.) recorded on the Screening/Enrollment Log.
The study funder (NIH) will not have access to the subject’s PHI. Only team members, as described
in item 21, will have access to this information.
Strategies: Diversity and reflection of regional population. Geographically, the clinics at the ACTRI
service a broad portion of the greater San Diego region. Moreover, we accept referrals from all over
Southern California. As a result, our study team will recruit patients from a highly diverse patient
population in terms of race, sex, and socioeconomic status. Subject populations in previous and


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ongoing studies have reflected the diversity of the region and disease-specific demographics. If we
are unable to obtain sufficient minority representation in our sample, under-represented racial groups
will be specifically targeted for recruitment.
Contingency plans: Should the above streams of recruitment prove inadequate for us to meet our
accrual timetable and keep our cohort schedule on track, we will reach out to social media and other
local print and multi-media-based advertisement strategies prominent within the San Diego area. This
approach has proved useful in past studies and should do so again. Participants will also be
reimbursed ($400) for successful study completion. This approach has been useful in motivating
participants to complete their study responsibilities in the past. If we find that the amount offered is
inadequate for maintaining active participant engagement, we will consider increasing it. This lab has
had a good track record with subject accrual and retention rates.
These recruitment plans have been very successful at attaining targeted sample sizes in previous
studies and have been recognized by UCSD and the NIH as appropriate models for recruitment
success. The Research Plan will be amended to include these recruitment strategies (and materials if
appropriate) as they are added but prior to their use.
12.
INFORMED CONSENT
Waiver of Documented Consent for Aiding in Determining Preliminary Eligibility during Research
Recruitment:
We are asking for a waiver of documented consent while recruiting patients to appropriately identify
potential participants with chronic low back pain during the phone screening procedure.
The phone screen is considered no more than low risk to the potential participants, since we will not
perform any procedure, and the probability and magnitude of harm or discomfort anticipated in this
research are not greater than those ordinarily encountered in daily life. In addition, our methods of
recruitment do not allow the pre-screener to directly contact or call the patient unless the patient,
themselves, contacts the study team first through contact information provided on study
advertisements or the patient’s treating physician refers them to the study.
The information inquired about and collected from the phone screen is necessary to ascertain the
potential participant’s suitability for entry into the study. While reviewing responses and information
during the phone screen, the screener may determine that the potential participant qualifies for the
study and then proceed to ask if they would be interested in participating. The screener will indicate to
potential participants that review of their medical records will be involved in determining formal study
eligibility.
Consenting Procedures:
Patients will be asked to provide written consent, using an IRB-approved consent form during their
first study session at the ACTRI. The consent process will take place prior to performing any study
related procedures and in a private room with the door closed. The study team member will describe
the study, including detailed information about risks and benefits, to potential participants. The study
team member will provide potential participants with an IRB-approved consent form. Potential
participants will be given ample time to read this consent form at the same visit or may take it with
them to read at another time. Potential study participants will be given the opportunity to ask and
receive answers to all questions they may have about the study, its risks and benefits, or the consent
form itself before signing the consent form. As this research is subject to HIPAA privacy rule
provisions, patients will also be requested to sign a separate HIPAA authorization for the use of
protected health information. The study team member will obtain informed consent in a language
understood by the prospective subject or their legally authorized representative, using certified
translations of study documents that will be uploaded for IRB review and approval upon the PI’s
receipt of IRB approval for the English version of the document. Certified translations of study
documents and qualified translators will be provided, where applicable.


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Potential participants who fulfill the eligibility criteria will be offered further participation in this study.
Only participants who have consented and provided HIPAA authorization will have identifiers or linked
information (e.g., subjects initials, study numbers, etc.) recorded on the Screening/Enrollment Log.
All signed consents will be maintained in marked binders, secured in locked filing cabinets within
private administrative offices at Dr. Zeidan’s Laboratory at the ACTRI. Documentation of this process
will be in written form and placed in the research record. A copy of the informed consent document
will be placed in the patient’s medical record, and a copy has been uploaded for IRB review and
approval.
The study consent form will include:
1.
Who is conducting the study
2.
Purpose of the study
3.
Why he/she is being asked to participate
4.
What will happen during the study
5.
The duration of the study
6.
Potential risks
7.
Potential of unforeseeable risks
8.
Alternatives to study participation
9.
Benefits reasonably expected
10.
Care if injured
11.
Costs to participate
12.
Payment for participation
13.
Voluntary nature of participation
14.
Extent confidentiality if maintained
15.
clinicaltrials.gov registry
16.
Provided time to ask and answer questions
17.
HIPAA discussion
13.
ALTERNATIVES TO STUDY PARTICIPATION
As this is not a treatment study, the only alternative to study participation is to not participate.
14.
POTENTIAL RISKS
This study may involve some risk, although the risks are considered low risk.
Straight Leg Raise Test
The straight leg raise test may produce the feeling of pain. The goal is to produce a targeted 30%
increase (2-point increase) in the feeling of pain for no more than 20 minutes. Although rare (less than
2% occurrence), participants may feel discomfort and/or pain for up to 24 hours. The study team will
ensure participants’ comfort and/or safety during this procedure. Importantly, participants will have
complete control of how much they raise their leg.
Reproductive Risks
Due to unknown risks and potential harm to the unborn fetus, sexually active women of childbearing
potential must use a reliable method of birth control while participating in this study.
Pregnant women are excluded from participation in this study. Because some methods of birth control
are not 100% reliable, a urine pregnancy test will be required at least 10 days from subjects’ last
normal menstrual period, if they are a sexually active woman of childbearing potential and not using
reliable birth control.
Randomization


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Participants will be instructed in the consent form with the following “You will be assigned to a study
group at random (by chance). Your assignment is based on chance rather than a medical decision
made by the researchers. The study group you are assigned to might not be the group you would
prefer to be in. Your assigned study group might also prove to be less effective or have more side
effects than the other study groups(s), or other treatments available for your condition. You will also
be randomly administered either naloxone or saline (or vice versa) in experimental sessions 6 and 7
which may influence some of their responses.”
Psychological Assessments
Participants may experience eye straining while completing psychological assessments. In this rare
case, we will adjust/increase the font size of our assessments on our electronic devices. Although this
has not occurred in our research studies, completing psychological assessments may increase
emotional distress. If this is the case, we will ask our participants to “take a break” or excuse
themselves from the study. We will also refer them to counseling services if need be. There may be a
perception of possible invasion of privacy or probing of information that might be considered sensitive.
To address this concern, all members of the research team will be sensitive to the needs of
participants by reminding them that they do not need to answer any questions that they would prefer
not to answer, complete any tasks that they would prefer not to complete, or follow through with any
procedure that they would rather decline. Study staff will use their clinical judgment to discontinue
assessment if a participant appears upset.
Respiratory Transducer and Pulse Oximeter
During the cLBP inducing procedure, the straight leg raise test, participants will be fitted with a
respiratory transducer around the chest. We have not experienced any problems with this device
however, participants may feel uncomfortable with the placing of this device. We will instruct
participants to inform us if that is the case, and we will make adjustments (tightening or loosening the
device’s placement).
Meditation Risks
Although extremely rare, long bouts of meditation practice (greater than 3-4 hours at a time), can
potentially lead to feelings of confusion, light-headedness, anxiety, sleepiness, and agitation. Further,
sitting for long periods of time could cause soreness in the body. Participants will be informed at the
beginning of each session that simply opening their eyes and moving could address all of these rare
risks.
Naloxone
The use of high naloxone is critically needed to comprehensively antagonize endogenous opioids.
This procedure is well-validated, largely safe in opioid free individuals and has reliably testing in a
number of studies. However, naloxone may also worsen or exacerbate feelings of nausea, vomiting,
sweating, increased heart rate, tremors, rapid breathing, and changes in body temperature, agitation,
and excitement. Although extremely rare, cardiac arrest may also occur as a function naloxone
infusion. Most of these side effects are mild and short-lived if they occur at all. Withdrawal symptoms
can arise if patients are taking opioids. Additional care will also be provided if any of these symptoms
exist. In our most recent psychophysical and pharmacologic study, 60 participants were administered
intravenous naloxone and there were 0 safety events or side effects reported.
In rare cases, naloxone may cause side effects such as: nausea or vomiting, sweating, increased
heart rate, tremor, rapid breathing, changes in body temperature, light-headedness, clouding of vision,
fainting, agitation and/or irritability, restlessness and/or excitement. Though they are highly unlikely to
occur, most of these side effects are mild and short-lived, if they occur at all. Naloxone has rarely
been associated with potentially fatal cardiac arrhythmias and even flagrant cardiac arrest. Additional
care will also be provided if any of these symptoms exist. Further, individuals with a history of syncope
and light headedness, fear of needles and blood are excluded from this study. The ACTRI nursing


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staff and/or a physician will oversee all experimental procedures where naloxone is involved to ensure
complete participant safety and comfort.
Thermal Stimuli
Thermal stimuli may elicit the feeling of pain and some temporary reddening of the skin. There is the
exceptionally rare potential to burning of the skin, although this has not occurred. To address this, we
never strap the probe to the limb (recommended use) and have customized a probe holder that will
allow the participant to escape at any time.
15.
RISK MANAGEMENT PROCEDURES AND ADEQUACY OF RESOURCES
The study was carefully designed to minimize or negate any potential risk/discomfort to participants.
An Independent Monitoring Committee (IMC) will monitor the activities of this study for purposes of
evaluating subject safety and study integrity. The key elements of the IMC plan include protection of
participant privacy, database protection, adverse event reporting, data quality and safety reports,
participant compliance, and safety review plans. For the proposed study, the IMC will review the
progress of and safety after 20, 40, 60 and 74 (if needed) study participants have completed all study
procedures. There will be no fee for the independent monitoring of the proposed studies. Dr. Zeidan
will oversee all experimental procedures of the proposed research activities. In the event of an
adverse safety event, protocol deviations and adverse events will be promptly (less than 24 hours)
reported to the IMC and the IRB.
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.
We do not anticipate any events that would cause a cessation of the study. We have repeatedly
demonstrated the ability to reliably recruit, retain, and execute data collection in a fashion that ensures
successful completion of our experiments.
However, in the unforeseeable case that the proposed study has to be stopped, the PI will include an
assessment of futility in the annual progress report to NIH. We will consult with the IMC and NCCIH to
assess the impact of significant data loss due to problems associated with stopping the study.
Straight Leg-Raise Test: The straight leg-raise test is a commonly employed maneuver to examine
chronic low-back pain severity and patient mobility. In the rare case that pain exacerbation is
increased by greater than 4 VAS points and does not return to baseline levels after 40 minutes, we
will discontinue patient study participation with reimbursement and a physician will evaluate the
participant.
Pregnancy: Due to unknown risks and potential harm to the unborn fetus, sexually active women of
childbearing potential must use a reliable method of birth control while participating in this study.
Pregnant women and nursing mothers are excluded from participation in this study. Because some
methods of birth control are not 100% reliable, a pregnancy test may be required at least 10 days
from a participant’s last normal menstrual period, if they are a sexually active woman of childbearing
potential.
Psychological Assessments: Although there are generally very low risks to completing psychological
scales, we will instruct (verbally; consent form) participants that psychological assessments may
produce emotional distress. A clinical psychologist may also be available to triage any concerns.


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Respiratory transducer: In order to reduce any discomfort from the respiratory transducer, we will
instruct participants to “let us know” when the belt is most comfortable and/or not comfortable.
Naloxone: Naloxone will be administered intravenously. Nausea or vomiting, sweating, increased
heart rate, tremor, rapid breathing, changes in body temperature; agitation and/or irritability,
restlessness and/or excitement are known side effects of taking naloxone. Most of these side effects
are mild and short-lived if they occur at all. Withdrawal symptoms can arise if patients are taking
opioids. Thus, before any naloxone/saline infusion testing session, we will administer an opiate
focused urine screening.
Thermal Stimuli: Participants will experience painful stimuli produced by heating the skin to
temperatures from 35°C to 49°C. Stimuli in this temperature range have been used extensively by the
PI and numerous laboratories around the world and do not produce tissue damage or burns. In order
to facilitate escape from the stimulator, the stimulator will be attached to a custom-designed thermal
stimulation probe holder. Participants will place their calf on top of the probe holder and will not be
strapped in or otherwise restrained. Therefore, participants will be able to simply lift their legs at any
time. Furthermore, stimulus temperature will be monitored continuously with an external digital chart
recorder that is independent of the microprocessor in the stimulator. Specifically, the unprocessed
output of the temperature sensor in the head of the stimulus probe will be both monitored and
recorded. In the event of a significant deviation from the target temperature, the TSA-II is designed to
shut off automatically. If the device does not shut itself off, the operator will terminate stimulation.
Furthermore, all volunteers will be conscious, lift their legs (respectively) from the probe, and will be
free to terminate the stimulus. In the remote event that a burn does occur, the affected area will be
gently rinsed with cold water and covered with a protective bandage. The participant will then be
referred to the burn clinic for treatment.
All study participants will provide informed consent. They will be reminded that their behavioral data is
confidential and that they can refuse to participate and/or withdraw from study participation without
explanation and financial reimbursement and this would not affect their respective relationship with
their physicians.
The proposed study will be conducted in a way that assures protection of the rights and welfare of
subjects. The ACTRI has an established history of successfully and safely completing clinical studies.
The proposed NIH sponsored 1-year project has plenty of time to ensure completion. The ACTRI is a
world-renown facility known for employing the highest standards of clinical research excellence. We
will conduct Sessions 1, 6, and 7 at this facility. All intervention sessions will be conducted at the
UCSD Center for Mindfulness, an established leader in conducting behavioral interventions. All
research staff will be trained to reliably conduct all activities. This project will include the study team
members noted in item 21 below. Due to the low risk of the study, we do not anticipate emergency
medical care services.
As in the naloxone studies previously conducted by this research lab, we are solely using an opiate-
focused urine drug screening as a precautionary measure to avoid any conflict, withdrawal, or side
effects that naloxone would elicit if a subject was presently using opiates/opioids. It is an eligibility
requirement that participants are not taking opioids. We will inquire about this thoroughly with each
participant through self-report and medical history confirmation, to ensure maximum safety.
Adverse Event: An AE is any problematic medical occurrence in a subject during participation in the
study.
The Office for Human Research Protections (OHRP) considers unanticipated problems involving risks
to


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subjects or others to include, in general, any incident, experience, or outcome that meets all of the
following criteria:
•
Unexpected in terms of nature, severity, or frequency given (a) the research procedures that
are described in the protocol-related documents, such as the IRB-approved research protocol and
informed consent document; and (b) the characteristics of the subject population being studied.
•
Related or possibly related to participation in the research (“possibly related” means there is a
reasonable possibility that the incident, experience, or outcome may have been caused by the
procedures involved in the research); and
•
Suggests that the research places subjects or others at a greater risk of harm (including
physical, psychological, economic, or social harm) than was previously known or recognized.
•
Any unanticipated problems, serious/unexpected adverse events, deviations or protocol
changes will be promptly reported to the IRB and IMC.
Serious Adverse Event (SAE)
A serious adverse event (SAE) is one that meets one or more of the following criteria:
•
Results in death
•
Is life-threatening (places the subject at immediate risk of death from the event as it occurred)
•
Results in inpatient hospitalization or prolongation of existing hospitalization
•
Results in a persistent or significant disability or incapacity
•
Results in a congenital anomaly or birth defect
An important medical event that may not result in death, be life threatening, or require hospitalization
may be considered an SAE when, based upon appropriate medical judgment, the event may
jeopardize the subject and may require medical or surgical intervention to prevent one of the
outcomes listed in this definition.
Time Period and Frequency for Event Assessment and Follow-Up: Unanticipated problems will be
recorded in the data collection system throughout the study. The PI will record all reportable events
with start dates occurring any time after informed consent is obtained until 7 (for non- serious AEs) or
30 days (for SAEs) after the last day of study participation. At each study visit, the PI will inquire about
the occurrence of AE/SAEs since the last visit. Events will be followed for outcome information until
resolution or stabilization.
To assess relationship of an event to study intervention, the following guidelines are used:
1.
Related (Possible, Probable, Definite)
1.
The event is known to occur with the study intervention.
2.
There is a temporal relationship between the intervention and event onset.
3.
The event abates when the intervention is discontinued.
4.
The event reappears upon a re-challenge with the intervention.
2.
Not Related (Unlikely, Not Related)
There is no temporal relationship between the intervention and event onset. An alternate etiology has
been established.
Expectedness of SAEs: The study PI and the IMC will be responsible for determining whether an SAE
is expected or unexpected. An adverse event will be considered unexpected if the nature, severity, or
frequency of the event is not consistent with the risk information previously described for the
intervention.
Severity of Event: The following scale will be used to grade adverse events:
Mild: no intervention required; no impact on activities of daily living (ADL)
Moderate: minimal, local, or non-invasive intervention indicated; moderate impact on ADL


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Severe: significant symptoms requiring invasive intervention; subject seeks medical attention, needs
major assistance with ADL
Reporting Procedures: SAEs that are unanticipated, serious, and possibly related to the study
intervention will be promptly reported by the principal investigator to the IRB and IMC. Anticipated or
unrelated SAEs will be handled in a less urgent manner but will be reported to the IMC, UCSD IRB,
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.
Confidentiality During Adverse Event (AE) Reporting: All adverse event (AE) reports and annual
summaries will not include subject or group-identifiable material. Each report will only include
subjects’ SIDs. Any unanticipated problems, serious and unexpected adverse events,
deviation/protocol changes will be promptly reported by the PI to the IRB and IMC. AE reports and
annual summaries will not include patient or group-identifiable material. Each report will only include
subjects’ SIDs.
Data and Safety Monitoring: The PI and the IMC will be responsible for the overall monitoring of the
data and safety of study participants. The PI will be assisted by other members of the study staff.
Reporting of Unanticipated Problems, Adverse Events or Deviations: Any unanticipated problems,
serious and unexpected adverse events, deviations or protocol changes will be promptly reported by
the PI or designated member of the research team to the IRB and NIH or appropriate government
agency if appropriate.
16.
PRIVACY AND CONFIDENTIALITY CONSIDERATIONS INCLUDING DATA ACCESS AND
MANAGEMENT
Study recruitment and enrollment will be monitored through a Screening/Enrollment Log, both created
as password protected Microsoft Excel spreadsheets.
The Screening/Enrollment Log will include a participant’s: name source of contact (community vs.
clinic), age, diagnosis (spinal pathology and date), gender, ethnicity, current drug regimen (i.e. mostly
focused on opiate usage), handedness and meditation experience. The Screening/Enrollment Log will
provide dates corresponding to when informed consent was obtained, the identified 2-point VAS
increase angle/height (from the straight leg raise test), height and weight on the day of the
screening/session 1, confirmed eligibility, as well as a note section for miscellaneous notations. This
information will be obtained from a phone screening and their responses will be logged into the
spreadsheet, where a judgment will be made regarding their suitability for entry into the study
according to study eligibility criteria.
The Screening/Enrollment Log will be analyzed in the interim between cohorts to determine which
input stream (community vs. clinical) yields the highest percentage of input to the study. This analysis
may prove useful for future tweaks of our recruiting strategies. We will also look at the stream
sourcing with respect to cohort diversity. Whenever possible, we will seek to maximize ethnic and
socioeconomic diversity in order to broaden the implications of the study’s results.The
No identifying information will be used on any study documents after enrollment. Enrolled participants
will be assigned a unique subject identification number (SID) that will be used on all CRFs and study
related documents after enrollment. The SID will be linked to participant identifiable information (as
described in item 9) in a separate Subject Identification Log, created and password protected in a
Microsoft excel spreadsheet. This will be stored on the coordinator’s password protected and
encrypted computer on the 3rd floor of the ACTRI.
All completed case report forms (CRF), created for all study related visit requirements, will kept in a
study binder at a central and secure location in our facility to better facilitate the tracking of each
enrolled participant and cohort. All study related documents with corresponding SIDs will be stored in


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a folder, in a larger cohort binder that’s divided by each individual participant. Each participant’s
binder will be monitored periodically (monthly) to ensure subject’s progress through the study as well
as positive or negative progression of symptoms of interest. All study-related safety and adverse
events will be reported to the UCSD Institutional Review Board (IRB) and IMC per appropriate
reporting timeframes. All study-related records/information will be made available to the UCSD IRB
and IMC at any time of their choosing.
All study data will be processed in a HIPPA-compliant fashion to ensure confidentiality and to protect
the PHI collected from improper use and/or disclosure. Digital data will be stored on both physically
and software protected computers and will only be accessed by study personnel from within the
ACTRI building (coordinator computer). Any reference to individual subjects in reports of this work will
utilize a study identification number (SID) to preserve confidentiality.
Following data collection participant identifying information will be destroyed when data collection and
corresponding statistical analyses for the primary aims are completed, consistent with data validation
and study design, producing an anonymous analytical data set. When these are complete, the study
coordinator(s) or PI will shred any and all physical documents containing any identifiers/PHI on it. Our
primary aim is to ensure participant safety and confidentiality; thus, we will take the highest measures
and uphold the most stringent standards to ensure patient confidentiality.
17.
POTENTIAL BENEFITS
This research is not expected to directly benefit individual participants, but is likely to yield
generalizable knowledge. The basic understanding of how mind body approaches function to alleviate
pain and improve wellbeing are unknown. The primary purpose of the proposed study is to determine
if endogenous opioidergic systems are engaged by mindfulness meditation to reduce chronic low
back pain. This work will also inform whether or not mind body approaches can be utilized in
combination with more traditional pain therapies by combining two distinct pain modulatory
processes/therapies. The knowledge gained from this study will provide novel mechanistic insight to
better develop and tailor cognitive therapeutic interventions to target multiple chronic pain conditions.
18.
RISK/BENEFIT RATIO
This study has a low risk, and the potential benefits of the proposed study outweigh the risks in terms
of overall reward. The knowledge to be gained significantly outweigh the low risks associated with this
study. In light of the ongoing opioid epidemic and the new prescribing guidelines by the Center for
Disease Control to employ non-opiate based therapies, the identification of the endogenous and
physiological mechanisms supporting such therapies is timely and of paramount importance. One
promising behavioral therapy is mindfulness-based meditation training. However, we still do not fully
appreciate how mindfulness reduces chronic pain. The primary purpose of this proposed study is to
determine if endogenous opioidergic systems are engaged by mindfulness meditation to reduce
chronic low back pain. Inquiry into this work may inform how mindfulness meditation can act as
effectively as leading prescribed opiates, providing an alternative non-pharmacological pain treatment
option. Importantly, if we replicate our findings in healthy individuals (i.e., mindfulness-based
analgesia is not opioidergically mediated), then the treatment of chronic pain may be more effective
with mindfulness and more conventional therapies due to a lack of cross-tolerance with opiate based
medications. Thus, the benefits significantly outweigh the low risks of this study.
19.
EXPENSE TO PARTICIPANT
Patients will have to pay $4 for parking for every visit to the ACTRI (3 visits to the ACTRI = $12), and
will be responsible for their own method of transportation.
20.
COMPENSATION FOR PARTICIPATION
Participants will not be compensated for parking but will receive $400.00 in pro-rated payments as
compensation for participation in this research. Participants will be paid with Vanilla Visa Gift Cards
after each attended study session. They will be paid $40 for each experimental session that pain
evoking procedures are used (3 sessions = $120). For each mindfulness session, they will be


Biomedical IRB Application Instructions
Page 22
compensated $10 (4 sessions = $40). For each session where naloxone/saline is administered, they
will be compensated $80 (2 sessions = $160). And upon study completion, they will also receive an
additional $80 for successfully completing all study sessions.
We believe that the modest stipend of $400 is appropriate without invoking coercion.
To receive payment, participants must provide their social security number, name and address in
compliance with IRS (Internal Revenue Service) reporting requirements. When payments are
reported to the IRS, the study team will not let them know what the payment is for, only that
participants have been paid. If participants do not wish to provide this information, they can still take
part in this study but will not be paid.
22.
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23.
FUNDING SUPPORT FOR THIS STUDY
The proposed study is an R21 funded by the National Center for Complementary and Integrative
Health (NCCIH). The grant will go through USCD as an existing grant. The corresponding program
officer at NCCIH for this grant will be Dr. Inna Belfer at inna.belfer@nih.gov, 301-435-1573.
24.
BIOLOGICAL MATERIALS TRANSFER AGREEMENT
Not applicable.
25.
INVESTIGATIONAL DRUG FACT SHEET AND IND/IDE HOLDER
IND Exemption Form (attached)
26.
IMPACT ON STAFF
Not applicable
27.
CONFLICT OF INTEREST
The PI and all key personnel report no conflicts of interest.
28.
SUPPLEMENTAL INSTRUCTIONS FOR CANCER-RELATED STUDIES
Not applicable
29.
OTHER APPROVALS/REGULATED MATERIALS
Not applicable


Biomedical IRB Application Instructions
Page 27
30.
PROCEDURES FOR SURROGATE CONSENT AND/OR DECISIONAL CAPACITY
ASSESSMENT
Not applicable

SAP_001.pdf: 
Title: Chronic Low Back Pain and Meditation  
NCT Record #: NCT04034004 
Date: May 3, 2023   
    
 
PI: Fadel Zeidan 
 
 
 
 
 


Sample Size Determination: Our targeted sample size is 60 cLBP patients (30/group). To conduct group 
comparisons among the two primary outcomes (naloxone + saline induced changes in pain ratings) and to 
ensure an overall type I error rate < 0.05, we used conservative Bonferroni corrections in all power 
calculations. Employing the pilot data corresponding to our previous work (Wells et al., 2020), we fit repeated 
measures ANOVA models that include indicator variables for group (mindfulness vs. non-mindfulness) and 
session (baseline vs. naloxone vs. saline). The estimated square root of mean square errors is 0.23 (23%) for 
pain ratings. Thirty subjects will provide 80% power to detect a pain rating difference of 22% between the 
naloxone and saline conditions in the non-mindfulness group with an estimated SD of 0.3 (30%). We expect no 
meaningful differences in pain reductions between naloxone and saline infusion during mindfulness meditation. 
Thus, we will have 80% power to detect a significant group X drug type interaction. Finally, 30 subjects/group 
will provide 80% power to detect a significant group difference of 19% for pain intensity. Such effect sizes 
parallel those observed in our pilot data (Wells et al., 2020).  
 
Primary outcomes 
• 
Numerical pain ratings while lying in the supine and in response to the straight leg raise test (SLR), 
respectively. 
 
Secondary outcomes 
 
• 
Brief Pain Inventory (BPI): interference and severity measures of chronic low back pain. 
 
• 
Pain Catastrophizing Scale (PCS): This is a 13-item assessment derived from definitions of 
catastrophizing. The PCS yields a total score and three subscale scores assessing rumination, 
magnification, and helplessness in subjects. 
 
• 
Roland-Morris Disability Questionnaire (RMDQ): This is a critical assessment for the chronic low back 
pain phenotype and was recommended for use by the NIH. 
 
• 
PROMIS 29-Item Profile: This is a 29-item generic health-related survey that assesses the following 7 
domains: depression, anxiety, physical function, pain interference, fatigue, sleep disturbance, and 
ability to participant in social roles/activities. 
 
Exploratory outcome 
 
• 
SF-12 Health Survey (SF-12): This is a 12-item version of the SF-36 item Health Survey designed to 
assess general mental and physical functioning, and overall health-related quality of life.    
 
Statistical Analysis Plan: To test the primary hypotheses, a 2 (group) X 2 (rest vs. manipulation) X 3 
(baseline vs. naloxone vs. saline) mixed model ANOVA will be employed to test differences in the change in 
pain from supine to straight leg raise test (SLR 1; SLR 2) within and across each testing session. Significant 
interactions will be explored using post-hoc paired simple effects tests to test the hypotheses that non-
mindfulness meditation but not mindfulness induced analgesia will be reversed by administration of naloxone 
but not saline. Between group comparisons will also be explored with simple effects tests. 
 
Secondary and exploratory outcomes will be assessed with a 2 (group) X 2 (baseline vs. post-intervention) by 
testing between and within group differences comparing baseline vs. post-study assessments. Simple effects 
tests will interpret significant main effects and interactions. 
 
 
Wells RE, Collier J, Posey G, Morgan A, Auman T, Strittmatter B, Magalhaes R, Adler-Neal A, McHaffie JG, 
Zeidan F (2020) Attention to breath sensations does not engage endogenous opioids to reduce pain. 
Pain 161:1884-1893.