Brain Effects of Opiate Agonist and Antagonist
Phase: PHASE4
Conditions: Chronic Low-back Pain
Sponsor: University of Rochester

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YALE UNIVERSITY
 HUMAN INVESTIGATION COMMITTEE
Application to Involve Human Subjects in Biomedical Research
100 FR1 (2015-2) 
SECTION I: ADMINISTRATIVE INFORMATION
Title of Research Project: 
 Brain effects of opiate agonist and antagonist
Principal Investigator: Paul Geha, MD
Yale Academic Appointment: 
Assistant Professor
Department: Psychiatry
Campus Address: 
290 Congress Ave. 
Campus Phone: 203-903-
4334
Fax: 203-624-4950
Pager: 
E-mail: paul.geha@yale.edu
Protocol Correspondent Name & Address (if different than PI):
Campus Phone: 
Fax: 
E-mail:
Yale Cancer Center CTO Protocol Correspondent Name & Address (if applicable):
Campus Phone: 
Fax: 
E-mail:
Business Manager:
Campus Phone :
Fax :
E-mail
Investigator Interests:
Does the principal investigator, or do any research personnel who are responsible for the design, 
conduct or reporting of this project or any of their family members (spouse or dependent child) 
have an incentive or interest, financial or otherwise, that may affect the protection of the human 
subjects involved in this project, the scientific objectivity of the research or its integrity? Note: 
The Principal Investigator (Project Director), upon consideration of the individual’s role and 
degree of independence in carrying out the work, will determine who is responsible for the 
design, conduct, or reporting of the research. 
Faculty Advisor:(required if PI is a student, 
resident, fellow or other trainee)          
 NA
Yale Academic Appointment:
Campus Address: 
Campus Phone: 
Fax: 
Pager: 
E-mail:
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See Disclosures and Management of Personal Interests in Human Research 
http://www.yale.edu/hrpp/policies/index.html#COI 
  Yes
No
Do you or does anyone on the research team who is determined by you to be responsible for the 
design, conduct or reporting of this research have any patent (sole right to make, use or sell an 
invention) or copyright (exclusive rights to an original work) interests related to this research 
protocol?
  Yes
  No
If yes to either question above, list names of the investigator or responsible person:
The Yale University Principal Investigator, all Yale University co-investigators, and all Yale 
University individuals who are responsible for the design, conduct or reporting of research must 
have a current disclosure form on file with the University’s Conflict of Interest Office. Yale New 
Haven Hospital personnel who are listed as co-investigators on a protocol with a Yale 
University Principal Investigator must also have a current financial disclosure form on file with 
the University’s Conflict of Interest Office. If this has not been done, the individual(s) should 
follow this link to the COI Office Website to complete the form:  http://www.yale.edu/coi/  
NOTE: The requirement for maintaining a current disclosure form on file with the University’s 
Conflict of Interest Office extends primarily to Yale University and Yale-New Haven Hospital 
personnel.  Whether or not they are required to maintain a disclosure form with the 
University’s Conflict of Interest Office, all investigators and individuals deemed otherwise 
responsible by the PI who are listed on the protocol are required to disclose to the PI any 
interests that are specific to this protocol.
SECTION II: GENERAL INFORMATION
1. Performing Organizations:  Identify the hospital, in-patient or outpatient facility, school or 
other agency that will serve as the location of the research.  Choose all that apply:
 
a. Internal Location[s] of the Study:
 Magnetic Resonance Research Center 
 Yale University PET Center
     (MR-TAC)   
 YCCI/Church Street Research Unit (CSRU)
 Yale Cancer Center/Clinical Trials Office (CTO)     YCCI/Hospital Research Unit (HRU)
 Yale Cancer Center/Smilow
 YCCI/Keck Laboratories
 Yale-New Haven Hospital
 Yale-New Haven Hospital—Saint Raphael Campus
 Cancer Data Repository/Tumor Registry
 Specify Other Yale Location:
b. External Location[s]:
 APT Foundation, Inc.
 Haskins Laboratories
 Connecticut Mental Health Center
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 John B. Pierce Laboratory, Inc.

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 Clinical Neuroscience Research Unit (CNRU) 
Veterans Affairs Hospital, West Haven
 Other Locations, Specify: 
 International Research Site 
(Specify location(s)):
c. Additional Required Documents (check all that apply):
 N/A
*YCCI-Scientific and Safety Committee (YCCI-SSC)
Approval Date: 
*Pediatric Protocol Review Committee (PPRC)
Approval Date: 
*YCC Protocol Review Committee (YRC-PRC)
Approval Date:
*Dept. of Veterans Affairs, West Haven VA HSS
Approval Date: 
*Radioactive Drug Research Committee (RDRC)
Approval Date: 
 YNHH-Radiation Safety Committee (YNHH-RSC)
Approval Date: 
 Yale University RSC (YU-RSC)
Approval Date:
 Magnetic Resonance Research Center PRC (MRRC-PRC)
Approval Date:
 *Nursing Research Committee
Approval Date:
 YSM/YNHH Cancer Data Repository (CaDR)
Approval Date: 
 Dept. of Lab Medicine request for services or specimens form
 Imaging on YNHH Diagnostic Radiology equipment request form (YDRCTO request) found at 
 http://radiology.yale.edu/research/ClinTrials.aspx)
*Approval from these committees is required before final HIC approval is granted. See instructions 
for documents required for initial submission and approval of the protocol. Allow sufficient time for 
these requests. Check with the oversight body for their time requirements.
2. Probable Duration of Project: State the expected duration of the project, including all 
follow-up and data analysis activities. 3 Years
3. Research Type/Phase: (Check all that apply)
a. Study Type
   
 Single Center Study
   
 Multi-Center Study
Does the Yale PI serve as the PI of the multi-site study? Yes 
No 
  
 Coordinating Center/Data Management
  
 Other: 
b. Study Phase
 N/A
    
 Pilot
 Phase I
 Phase II
 Phase III
 Phase IV
    
 Other (Specify) 
4. Area of Research: (Check all that apply) Note that these are overlapping definitions and 
more than one category may apply to your research protocol. Definitions for the following 
can be found  in the instructions section 4c:
 Clinical Research: Patient-Oriented
  
 Clinical Research: Outcomes and 
 Clinical Research: Epidemiologic and Behavioral 
                Health Services
 Translational Research #1 (“Bench-to-Bedside”)    
 Interdisciplinary Research
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 Translational Research #2 (“Bedside-to-Community”) 
 Community-Based Research
5.   Is this study a clinical trial? Yes 
No 
NOTE the current ICMJE (International Committee of Medical Journal Editors) definition of a 
clinical trial: “any research study that prospectively assigns human participants or groups of humans 
to one or more health-related interventions to evaluate the effects on health outcomes.” Health-related 
interventions include any intervention used to modify a biomedical or health-related outcome (for 
example, drugs, surgical procedures, devices, behavioral treatments, dietary interventions, and 
process-of-care changes). Health outcomes include any biomedical or health-related measures 
obtained in patients or participants, including pharmacokinetic measures and adverse events”
If yes, where is it registered?
Clinical Trials.gov registry 
Other (Specify) 
Registration of clinical trials at their initiation is required by the FDA, NIH and by the ICMJE.
If this study is registered on clinicaltrials.gov, there is new language in the consent form and compound 
authorization that should be used.
For more information on registering clinical trials, including whether your trial must be 
registered, see the YCCI webpage, http://ycci.yale.edu/researchers/ors/registerstudy.aspx or 
 contact YCCI at 203.785.3482)
6. Does the Clinical Trials Agreement (CTA) require compliance with ICH GCP (E6)? 
Yes 
 No
7. Will this study have a billable service? A billable service is defined as any service rendered to 
a study subject that, if he/she was not on a study, would normally generate a bill from either 
Yale-New Haven Hospital or Yale Medical Group to the patient or the patient’s insurer. The 
service may or may not be performed by the research staff on your study, but may be provided by 
professionals within either Yale-New Haven Hospital or Yale Medical Group (examples include 
x-rays, MRIs, CT scans, specimens sent to central labs, or specimens sent to pathology). Notes: 
1. There is no distinction made whether the service is paid for by the subject or their insurance 
(Standard of Care) or by the study’s funding mechanism (Research Sponsored). 2. This generally 
includes new services or orders placed in EPIC for research subjects. 
Yes 
 No
 If answered, “yes”, this study will need to be set up in OnCore, Yale’s clinical research 
management system, for Epic to appropriately route research related charges. Please contact 
oncore.support@yale.edu
8. Are there any procedures involved in this protocol that will be performed at YNHH or one of 
its affiliated entities? No ___  If Yes, please answer questions a through c and note instructions 
below.  If No, proceed to Section III.
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a. Does your YNHH privilege delineation currently include the specific procedure that you will 
perform? Yes
b. Will you be using any new equipment or equipment that you have not used in the past for 
this procedure? No
 
c. Will a novel approach using existing equipment be applied? No
 
If you answered “no” to question 8a, or "yes" to question 8b or c, please contact the YNHH 
Department of Physician Services (688-2615) for prior approval before commencing with your 
research protocol.
Please note that if this protocol includes Yale-New Haven Hospital patients, including patients at 
the HRU, the Principal Investigator and any co-investigators who are physicians or  mid-level 
practitioners (includes PAs, APRNs, psychologists and speech pathologists) who may have direct 
patient contact with patients on YNHH premises must have medical staff appointment and 
appropriate clinical privileges at YNHH. If you are uncertain whether the study personnel meet 
the criteria, please telephone the Physician Services Department at 203-688-2615. By signing 
this protocol as a PI, you attest that you and any co-investigator who may have patient contact 
has a medical staff appointment and appropriate clinical privileges at YNHH.
SECTION III: FUNDING, RESEARCH TEAM AND TRAINING
1. Funding Source: Indicate all of the funding source(s) for this study. Check all boxes that apply.
Provide information regarding the external funding source.  This information should include 
identification of the agency/sponsor, the funding mechanism (grant or contract), and whether 
the award is pending or has been awarded. Provide the M/C# and Agency name (if grant-
funded).  If the funding source associated with a protocol is “pending” at the time of the 
protocol submission to the HIC (as is the case for most NIH submissions), the PI should note 
“Pending” in the appropriate section of the protocol application, provide the M/C# and 
Agency name (if grant-funded) and further note that University (departmental) funds support 
the research (until such time that an award is made).  
PI 
Title of Grant
Name of Funding Source 
Funding
Funding Mechanism
Paul Geha, MD
Neural Mechanisms 
of Obesity in 
Chronic Low Back 
Pain
NIDA
  Federal
  State
  Non Profit
  Industry
  Other For 
Profit 
  Other
Grant-M#           
Contract# 
Contract Pending
  Investigator/Department 
Initiated
  Sponsor Initiated
  Other, Specify:
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  Federal
  State
  Non Profit
  Industry
  Other For 
Profit 
  Other
Grant-M#           
Contract# 
Contract Pending
  Investigator/Department 
Initiated
  Sponsor Initiated
  Other, Specify:
  Federal
  State
  Non Profit
  Industry
  Other For 
Profit 
  Other
Grant-M#           
Contract# 
Contract Pending
  Investigator/Department 
Initiated
  Sponsor Initiated
  Other, Specify: 
IRB Review fees are charged for projects funded by Industry or Other For-Profit Sponsors.  
Provide the Name and Address of the Sponsor Representative to whom the invoice should be 
sent.  Note: the PI’s home department will be billed if this information is not provided.
Send IRB Review Fee Invoice To:
Name:
Company:
Address:
2. Research Team:  List all members of the research team. Indicate under the affiliation column whether 
the investigators or study personnel are part of the Yale faculty or staff, or part of the faculty or staff 
from a collaborating institution, or are not formally affiliated with any institution. ALL members of 
the research team MUST complete Human Subject Protection Training (HSPT) and Health 
Insurance Portability and Accountability Act (HIPAA) Training before they may be listed on the 
protocol.  See NOTE below.
NOTE: The HIC will remove from the protocol any personnel who have not completed required training. 
A personnel protocol amendment will need to be submitted when training is completed.
Name
Affiliation: Yale/Other 
Institution (Identify)
NetID
Principal Investigator 
Paul Geha
Yale
PYG5
Role: Co-PI
Dana Small
Yale
DS537
Role: RA
Gelsina Stanley
John B. Pierce
Gs558
Role:RA
Elizabeth Garcia
John B. Pierce
Eg559
Role : Student
William Oles
Yale
wco5
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SECTION IV:
 PRINCIPAL INVESTIGATOR/FACULTY ADVISOR/ DEPARTMENT CHAIR AGREEMENT
As the principal investigator of this research project, I certify that:

The information provided in this application is complete and accurate.

I assume full responsibility for the protection of human subjects and the proper conduct of the
      research.

Subject safety will be of paramount concern, and every effort will be made to protect subjects’
      rights and welfare.

The research will be performed according to ethical principles and in compliance with all federal,
      state and local laws, as well as institutional regulations and policies regarding the protection of  
      human subjects.

All members of the research team will be kept apprised of research goals.

I will obtain approval for this research study and any subsequent revisions prior to my initiating the
      study or any change and I will obtain continuing approval of this study prior to the expiration date     
      of any approval period.

I will report to the HIC any serious injuries and/or other unanticipated problems involving risk to
      participants.

I am in compliance with the requirements set by the University and qualify to serve as the
      principal investigator of this project or have acquired the appropriate approval from the 
      Dean’s Office or Office of the Provost, or the Human Subject Protection Administrator at
      Yale-New Haven Hospital, or have a faculty advisor.

I will identify a qualified successor should I cease my role as principal investigator and facilitate a
smooth transfer of investigator responsibilities.
_____
 
PI Name (PRINT) and Signature
Date
As the faculty advisor of this research project, I certify that:

The information provided in this application is complete and accurate.

This project has scientific value and merit and that the student or trainee investigator has the necessary 
resources to complete the project and achieve the aims.

I will train the student investigator in matters of appropriate research compliance, protection of human 
subjects and proper conduct of research.

The research will be performed according to ethical principles and in compliance with all federal, state and 
local laws, as well as institutional regulations and policies regarding the protection of human subjects.

The student investigator will obtain approval for this research study and any subsequent revisions prior to 
initiating the study or revision and will obtain continuing approval prior to the expiration of any approval 
period.

The student investigator will report to the HIC any serious injuries and/or other unanticipated       problems 
involving risk to participants. 

I am in compliance with the requirements set forth by the University and qualify to serve as       the faculty 
advisor of this project. 

I assume all of the roles and responsibilities of a Principal Investigator even though the student may be 
called a PI.
___________
______
_____
    Advisor Name (PRINT) and Signature
Date
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Department Chair’s Assurance Statement
Do you know of any real or apparent institutional conflict of interest (e.g., Yale ownership of a
sponsoring company, patents, licensure) associated with this research project?
 Yes (provide a description of that interest in a separate letter addressed to the HIC.)
 No
As Chair, do you have any real or apparent protocol-specific conflict of interest between yourself and
the sponsor of the research project, or its competitor or any interest in any intervention and/or method
tested in the project that might compromise this research project?
Yes (provide a description of that interest in a separate letter addressed to the HIC)
No
I assure the HIC that the principal investigator and all members of the research team are qualified by
education, training, licensure and/or experience to assume participation in the conduct of this research
trial. I also assure that the principal investigator has departmental support and sufficient resources to
conduct this trial appropriately.
   ____________________________
   Chair Name (PRINT) and Signature  
    
 Date
   _________________________________
   Department
YNHH Human Subjects Protection Administrator Assurance Statement
Required when the study is conducted solely at YNHH by YNHH health care providers.
As Human Subject Protection Administrator (HSPA) for YNHH, I certify that:

I have read a copy of the protocol and approve it being conducted at YNHH.

I agree to notify the IRB if I am aware of any real or apparent institutional conflict of interest.

The principal investigator of this study is qualified to serve as P.I. and has the support of the hospital 
for this research project.
  ______________________________________
    YNHH HSPA Name (PRINT) and Signature       
Date
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SECTION V: RESEARCH PLAN
1. Statement of Purpose: State the scientific aim (s) of the study, or the hypotheses to be 
tested. 
To determine the effect of one dose of morphine, naltrexone and placebo on brain activity in 
healthy participants and patients suffering from pain.
To determine whether the effect of one dose of morphine, /naltrexone and placebo on brain 
activity in healthy participants and patients suffering from pain is different depending on 
Single Nucleotide Polymorphism (SNP) at the gene loci coding for opiate and dopamine 
related neurotransmission.  
To relate brain response to morphine to performance on reward related decision-making 
tasks.
2. Background: Describe the background information that led to the plan for this project. 
Provide references to support the expectation of obtaining useful scientific data.
Opiate medications such as morphine are potent analgesics and frequently used in the 
treatment of chronic non-cancer pain despite the absence of benefits in randomized clinical trials 
on pain relief when compared to placebo beyond 3-4 months of treatment 1. Treatment with 
opiates put patients at risk of weight gain 2,3, falls 4, overdose, abuse and long-term dependence 5.
Opiate intake has been particularly associated with a shift in the diet towards increased sugar 
and highly palatable food intake and long-term weight gain 6,7. In addition, opiate antagonist 
such as naltrexone is used to prevent binge eating behavior in humans, which is a major 
contributor to obesity 8. Extensive animal research is consistent with a major role of μ-opiate 
agonist in feeding in the absence of hunger (i.e. hedonic feeding) (comprehensive reviews in 
9,10).  Binding of μ-opiate agonist in the ventral striatum and amygdala causes hyperphagia in 
non-hungry animals and shifts their preference towards highly palatable fat 11,12. 
Chronic low back pain (CBP) is associated with obesity 13-17; however, the contribution of 
opiate prescriptions to increased body weight is still unknown.  Our preliminary data show that 
CBP patients treated with opiate based medications have a decreased brain response to 
milkshake when compared to CBP patients not on opiate in the whole insular cortex and primary 
somatosensory motor areas (Figure 1). This suggests that CBP patients on opiates might have a 
decreased orosensory experience during food ingestion since insula contains the primary taste 
cortex 18 and integrates taste perception with internal state such as hunger or pain 19. This 
decreased perception of food might in turn lead to long-term weight gain.
Given the lack of studies comparing brain response of CBP patients treated with opiate 
medications during food ingestion to CBP patients without opiate treatment we cannot tell 
whether the functional changes we observe in Figure 1 are due to an acute effect of opiate 
medications or due to a long-term adaptations to these drugs.  It is therefore possible that acute 
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administration of opiate may at first lead to increased response to milkshake that would later 
adapt and decrease upon chronic administration.
Binding of morphine in the brain of healthy participants occurs in areas rich in opioid receptors 
including ventral striatum, amygdala, and medial prefrontal cortex 20-22. These areas have been 
shown to mediate reward related decision making including food 23-25 money, and goods 26,27.  In 
addition, there is evidence that morphine binding in these areas strongly modulates deicision 
making about food 28 and money29. Hence, it stands to reason that inter-individual response 
differenes to one dose of morphine could relate to inter-individuals differences on reward related 
decision-making. 
Therefore, as a first step, we would like to understand the effect of acute administration 
of a μ-opiate agonist (i.e. morphine), a μ-opiate antagonist (i.e. naltrexone) on brain activity at 
rest and in response to food in comparison to the administration of a placebo in a double blind 
design.  Also we would like to study the acute effects of opioid (morphine) administration in an 
open label arm. We are adding this arm to generate preliminary results to study the effect of 
Morphine using a simpler and less time consuming protocol where participation would be easier 
for subjects. We will relate performance on gambling, motivational and risk taking tasks to brain 
response to morphine.
 In addition, we would like to factor in individual genetic differences in dopamine and opiate 
neurotransmission since these are well known to affect brain response to opiates 20,30.
Z – score = 2.3 
 7
Figure 1.  Results of a T-test comparison of brain response to milkshake (corrected for tasteless) 
between 6 CBP patients taking opiates and 7 CBP patients not taking any analgesic medications. 
The two groups did not differ on their ratings of pain intensity. Results shown at Z > 2.3 and p < 
0.05 corrected for multiple comparisons and using random effects model. We observed 
decreased brain response with opiate treatment in the right insula, primary somatomotor/sensory 
areas and frontal operculum. 
3. Research Plan: Summarize the study design and research procedures using non-technical 
language that can be readily understood by someone outside the discipline. Be sure to 
distinguish between standard of care vs. research procedures when applicable, and 
include any flowcharts of visits specifying their individual times and lengths. Describe 
the setting in which the research will take place.
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Procedure:
A. Description of the of the procedures for the double blind placebo controlled arm
Day 1) Phone screening 
During an initial telephone conversation, we will provide a brief description of the study, do an 
initial screening of the subject to ensure that they meet inclusion criteria and do not possess any 
of the exclusion criteria, and schedule the subject's intake session.  
Day 2) Intake session
Subject comes to The John B Pierce Laboratory where written informed consent will be 
obtained. The subject will be asked to refrain from alcohol use the day before any session. The 
subject then completes a subset of the following intake measures to determine eligibility:  
A. Toxicology/pregnancy screening
We will perform the following screens:
i.
Breath alcohol levels will be assessed with the Alcohawk Elite Breathalyzer. 
ii.
Urine toxicology screens will be conducted using the Integrated E-Z Split Key Cup II 
(Innovacon Inc., San Diego, CA) for opiates, cocaine, THC, PCP and barbiturate. 
iii.
We do not wish to study females who may be pregnant.  Therefore, all females of 
childbearing potential will be given a urine pregnancy test.
If a subject tests positive on any of these screens they will be informed of the result and excluded 
from further participation in the study. The results from these tests will not be recorded for 
subjects who are excluded for positive results.
Genotyping:
We will collect a saliva sample to genotype for SNPs related to dopaminergic and opiate 
signaling in the brain. The gene loci tested and their SNPs are attached.
Iowa Gambling Game: 
Iowa Gambling Task31: Designed to evaluate the ability to postpone immediate reward for a 
longer-term successful outcome, tests emotional decision-making ability. Subjects play a card 
game under conditions of limited knowledge about reward and penalty. The participant is 
presented with 4 decks of card.  Two decks are advantageous (A and B); A and B do not give big 
gains but do not lead to losses after 100 draws.  Two decks are disadvantageous (C and D).  C 
and D give big gains but end up 
leading to big losses after 100 draws.  
Patients 
with 
inability 
to 
delay 
immediate gratification to improve 
long-term outcomes perform badly on 
this task.   The gains and losses will be 
in fake Monopoly money.
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Effort Expenditure for Rewards (EEfRT) 
The EEfRT 32task is a multi-trial game in which participants are given an opportunity on each 
trial to choose between two different task difficulty levels in order to obtain monetary rewards 
(see Figure) For all trials, participants made repeated manual button presses within a short period 
of time. Each button press raised the level of a virtual “bar” viewed onscreen by the participant. 
Participants are eligible to win the money allotted for each trial if they raised the bar to the “top” 
within the prescribed time period. Each trial presented the subject with a choice between two 
levels of task difficulty, a ‘hard task’ and an ‘easy task’. Successful completion of hard-task 
trials required the subject to make 100 button presses, using the non-dominant little finger within 
21 seconds, while successful completion of easy-task trials required the subject to make 30 
button presses, using the dominant index finger within 7 seconds.
For easy-task trials, subjects are eligible to win the same amount, $1.00, on each trial if they 
successfully completed the task. For hard-task choices, subjects are eligible to win higher 
amounts that varied per trial within a range of $1.24 – $4.30 (“reward magnitude”). Subjects are 
not guaranteed to win the reward if they complete the task; some trials are “win” trials, in which 
the subject receive the stated reward amount, while others are “no win” trials, in which the 
subject receive no money for that trial. To help subjects determine which trials are more likely to 
be winning trials, subjects are provided with accurate probability cues at the beginning of each 
trial. Trials had three levels of probability: “high” 88% probability of being a win trial, 
“medium” 50% and “low” 12%. Probability levels always applied to both the hard task and easy 
task, and there are equal proportions of each probability level across the experiment. Each level 
of probability appeared once in conjunction with each level of reward value for the hard task. All 
subjects received trials presented in the same randomized order.
All trials begin with a 1-second fixation cross, following a 5-second choice period in which 
subjects are presented with information regarding the probability of receiving reward and the 
reward magnitude of the hard task. Subjects are told that if they did not make a choice within 5 
seconds, they would be randomly assigned to either the easy or the hard task for that trial. After 
making a choice, subjects are then shown a 1-second “Ready” screen and then completed the 
task. Following task completion, subjects are shown a 2 second feedback screen informing them 
that the task was successfully or unsuccessfully completed. If subjects successfully completed 
the task, then a second feedback screen appeared for 2 seconds in which subjects are told 
whether they had won money for that trial (reward feedback). In total, easy-task trials took 
approximately 15 seconds, whereas hard-task trials took approximately 30 seconds.
Subjects are told that they would receive a base-rate of compensation for their participation. In 
addition, they are told that two of their win trials would be randomly selected at the end of the 
experiment as “incentive trials,” for which they would receive the actual amount won on those 
trials. Subjects are informed that they had twenty minutes to play as many trials as they could. 
Since hard-task trials take approximately twice as much time to complete as easy-task trials, the 
number of trials that the subject was able to play depended in part on the choices that he or she 
made. This meant that making more hard-task trials toward the beginning of the experiment 
could reduce the total number of trials, which could in turn mean that the subject would not get a 
chance to play high-value, high-probability trials that might have appeared towards the end of 
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the playing time. This trade-off will be explained clearly to the subject. Importantly, subjects are 
not provided with any information regarding the distribution of trial types. The goal of this trade-
off is to ensure that neither a strategy of always choosing the easy or the hard option could lead 
to an ‘optimal’ performance on the task. Moreover, the complexity of variables (with varying 
monetary reward levels, probability, and loss of time for future trials), does not lend itself to a 
formal calculation of an optimal response selection, and subjects are required to make decisions 
within a brief amount of time. This was done to help ensure that subject decisions reflected 
individual differences in the willingness to expend effort for a given level of expected reward 
value.  At the end of the experiment the subjects will receive the accumulated earnings in real 
money.
The EEfRT was programmed in Matlab (Matlab for Windows, Rel. 2007b. Mathworks Inc., 
Natick, MA) using the Psychtoolbox version 2.0.
Decision making under uncertainty and risk
Participants 
will 
receive 
detailed 
explanations of the task26 and of the bonus 
payment 
(i.e. 
accumulated 
earnings) 
procedure and are required to pass task 
comprehension questions before completing 
practice trials. In the experiment itself, 
participants will be first given $100 
endowment to start playing. They will make 
60 binary choices between a certain gain of 
$5 and a bet of a monetary value (20 
amounts: $5–$20 in gains or losses) and 
probability of payout or loss (3 levels: 0.25, 0.5, 0.75) are systematically manipulated. Each trial 
will be represented by an image of a bag containing 100 colored poker chips, some red and some 
blue (See Figure); these images corresponded to physical bags that are present in the 
experimental room. The size of the colored areas and the numbers written inside indicate the 
number of chips of each color in the bag. Above and below each color, a number indicate how 
much a chip of that color would be worth if it are drawn from the bag.  Trial order will be 
randomized independently for each participant.  At the end of the experiment the subjects will 
receive the accumulated earnings in real money if they win money in addition to the $100.  If 
they lose money they will still receive a $100 for participation. 
Equipment training:
fMRI training
Subjects will be asked to lie in our fMRI simulator and will be outfitted with the taste 
delivery device and earphones that will play simulated fMRI scanner noises. The simulator 
consists of a padded table on which the subject lies supine. A removable wooden replica of 
the fMRI headcoil is placed over the subjects’ head. The gustatory manifold is anchored to 
the simulated headcoil. New tubing and syringes are used for each subject and the 
 a) Example trial representing a 25, 50, 75% chance of 
gaining $15, $7, $30, respectively. (b) Example trial 
sequence.
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mouthpiece and nasal mask are cleaned and sterilized between uses by boiling in a 10% 
bleach solution for 15 min.  In the simulator and in the actual fMRI scanner subjects will 
receive liquids through an fMRI compatible custom designed gustometer built by Dr. Small 
(in collaboration with colleagues in the Pierce shop). In brief, the gustometer consists of a 
computer running Matlab, controlling a series of programmable syringe pumps with 60ml 
syringes and beverage tubing attached and leading to a mouthpiece (gustatory manifold) held 
in place by anchoring to the fMRI headcoil. This set up has been used successfully by Dr. 
Small’s lab for the past 9 years33-35. All subjects will undergo a 10-minute mock fMRI run in 
which they receive the following stimuli:  sucrose, tasteless, and milkshake. The purpose of 
this mock run is to familiarize subjects with the procedures of the fMRI experiment and to 
teach subjects how to comfortably swallow while lying on a bed made to look like the MR 
scanner. Most people have no difficulty learning to swallow small quantities of liquid while 
lying down. Subjects who have difficulty with supine swallowing, who are uncomfortable in 
the simulated MRI environment, or unable to swallow without excessive movement will not 
be asked to continue participating in the studies. This procedure takes 30 minutes. 
Meeting with the Physician and discussion of drug side effects:
Each participant will meet with Dr. Paul Geha to go over the possible side effects of 30 mg 
of Morphine, 50 mg of Naltrexone and placebo given at one dose.  Dr. Geha will go over the 
most common side effects and will emphasize the risk of altered mental status (e.g. 
sleepiness, drowsiness) after one dose of morphine. Dr. Geha is Yale trained psychiatrist and 
will collect psychiatric history on possible previous misuse of alcohol, illegal drugs and 
prescription drugs.  Any subject with such previous history will be excluded from the study.  
In addition, each participant will be given a patient information sheet about each of the 
medications used in the study.
To avoid fatigue subjects will take a 5-minute breaks every 15-20 minutes. This session takes 
about 2 hours. If the subject meets all eligibility criteria we will schedule them for a Pre-
supplementation session at The John B Pierce Laboratory. 
Measurment of body fat composition:
We will measure body fat composition of our participants; body fat and body mass index can be 
confounding in our analysis given that brain response to food is different between obese and 
healthy weight participants36.  The BodPod body composition tracking system is an air 
displacement plethysmograph which uses whole-body densitometry to determine body 
composition (fat and fat-free mass).The BodPod is an egg-shaped pod that consists out of two 
chambers. The front, or Test chamber, is where the subject sits and is comprised of a seat that 
forms a common wall separating it from the rear, or reference chamber. During the brief data 
collection period of the volume measurement, the chamber door is secured by a series of 
electromagnets and a gasket. A diaphragm is mounted on the common wall, which oscillates 
during testing. This causes small changes in volume inside the chamber, of which the pressure 
response to these small volume changes is measured. This is done by measuring the interior 
volume of the empty BodPod chamber, then measuring it again when the subject is seated inside. 
By subtraction, the subject's body volume is obtained. Once the subject's mass and volume are 
determined, body density is calculated and the relative proportions of fat and fat-free mass are 
determined. Thus this procedure is entirely non-invasive. A complete test requires about 5 
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minutes for which the subject will be asked to change into spandex undergarments, that are 
provided by the Small lab. The interior of the BodPod accommodates a wide variety of human 
shapes and sizes, including subjects up to 7 feet tall and 550 pounds. The egg-shaped design of 
the BodPod maximizes interior space, and can be used routinely for testing a wide variety of 
subjects, including special populations such as obese subjects. The BodPod's precision, accuracy, 
and reliability have been validated through independent research studies with various subject 
populations. The Bioelectric Impedance Analysis device (BIA) uses the flow of various low 
alternating electrical currents and measures impedance.  It produces estimates of total body 
water, extracellular water, fat-free mass and lean soft tissue for each limb and torso. It consists of 
a weighing platform that also contains foot electrodes (that the subject steps onto) and a bar with 
finger electrodes (that the subject holds onto with their hands). A complete measurement takes 
under 1 minute and does not require a subject to change into separate garments. This system is 
routinely used in hospitals, medical practices and inpatient care facilities in accordance with 
regulations. The BIA’s precision, accuracy and reliability have been validated through 
independent research studies.
Below is a list of questionnaires subjects will fill out and a description of the food reinforcement 
test:
Binge Eating Scale (BES): The BES is a 16-item questionnaire that will assess behavioral 
manifestations and feelings surrounding a binge episode . 
Dutch Eating Behavior Questionnaire (DEBQ): The DEBQ (33 items) will be used to assess 
emotional eating, externalizing, and dietary restraint.
Three Factor Eating Questionnaire (TFEQ): This 58-item questionnaire will be used to obtain 
a score on the subscales of “cognitive control of eating”, “disinhibition”, and “susceptibility to 
hunger”37.
International Phsyical Activity Questionnaire (IPAQ): the IPAQ is a 27-item questionnaire 
that will be used to obtain an estimate of physical activity 38.
Pittsburgh Sleep Quality Index (PSQI): the PSQI is a 19-item questionnaire with a global 
score and subscales that include sleep quality, latency, duration, sleep efficiency, disturbances, 
hypnotic use, and daytime dysfunction 39.
Dieting and Weight History Questionnaire: This questionnaire will be used to assess history 
of weight and weight loss attempts.
Power of Food Scale (PFS): The PFS is an 18-item questionnaire that will asses the 
psychological influences of food environment 40.
Night Eating Questionnaire: This 16-item questionnaire will be used to characterize night 
time eating behaviors 41. 
Phenotype Questionnaire: 11-item questionnaire that assesses individual eating habits and 
attitudes towards food.
The Behavioral Inhibition System/Behavioral Activation System (BIS/BAS; will assess 
behavioral activation and behavioral inhibition which have been proposed as biological systems 
underlying behavior and affect. The Behavioral Inhibition assesses sensitivity to punishment 
(BIS scale) and three subscales tap different components of behavioral activation (Reward 
Responsiveness, Drive and Fun Seeking). This measure has been shown to have good 
convergent, discriminant, and predictive validity in which the instrument measures sensitivity 
rather than the person’s typical experiences.  The Behavioral Inhibition Scale will be used to tap 
the component of impulsivity related to decreased sensitivity to the negative consequences of 
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behavior and has been shown to predict nervousness in anticipation of an impending punishment 
42.
Yale Food Addiction Scale (YFAS) :  will assess participants’s food addiction43.
UPPS Impulsive Behavior Scale: will assess participants impulsivity 44,45
Barratt Impulsivity Scale: will assess participants impulsivity46
The Short Form of the McGill Pain Questionnaire (SFMPQ): will assess pain intensity and 
different sensory and affective dimensions of pain47. 
Neuropathic Pain Scale:  will assess pain intensity and different types of sensory properties of 
pain48.
The pain DETECT questionnaire: will assess the neuropathic component of low back pain49.
Beck’s Anxiety Inventory and Beck’s Depression Inventory: will assess mood and anxiety scores 
50,51
Positive and Negative Affect (PANAS): will assess participants affect52.
Pain Catastrophizing Scale: will assess pain “catastrophizing”53.  
Pain Disability Index: will assess to what extent patients are disabled from pain54.
Day 3) fMRI scan session
1. Upon arrival to the Magnetic Resonance Research Center (MRRC) participants a urine drug 
test will be obtained as well as Breath alcohol levels will be assessed with the Alcohawk 
Elite Breathalyzer.  If any of these tests are positive the study will be cancelled.  Next, vitals 
signs (VS)(blood pressure, heart rate, respiratory rate, pulse oximetry, and temperature).  If 
the urine drug test is positive for opiates or methadone the study will be cancelled and the 
subject disqualified for this study. 
2. Participants with BP < 90/60 and/or heart rate < 60 will be excluded and the study will be 
cancelled.  VS will be logged in to a VS sheet and kept with the participant paper record in 
our study binders.  Mental and neurologic status will be assessed for a baseline using the 
National Institutes of Health (NIH) Stroke Scale Neurological Assessment flow sheet (see 
attached form).
3. Next  20 ml of blood will be withdrawn.   All blood samples will be placed in pre-chilled test 
tubes, and centrifuged at 4 C and the plasma stored at -70 C until analyzed according to 
standard procedures in the YCCI Core Laboratory
4. Next, participants will be undergo fMRI scanning:
fMRI session: Set up is as above for fMRI simulator in fMRI training. Prior to getting the 
subject into the MR-room all people involved with the study walk through a detector 
designed to detect metal objects. We will use a Siemens 3T Trio TIM scanner with a 32-
channel head-coil. A T1-weighted 3D MPRAGE sequence (4 minutes) will be performed to 
obtain a high-resolution anatomical image and echoplanar imaging will be used to measure 
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the BOLD signal as an indication of cerebral activation in response to various tastes 
(milkshake and tasteless) during two 9.6-minute runs and in response to sucrose and tasteless 
during two 9.6-minute runs. A run consists of multiple blocks of taste (milkshake or 
tasteless). One block is a series of 4 – 8 presentations of tastes or tasteless; Each presentation 
starts with a 0.75 cc delivery of liquid over 2 s followed by 7 s in which to swallow. Each 
taste block is followed by a rinse (0.75 cc deionized water). Before the start of a new block 
there is a rest period of 10 seconds. Blocks vary in length between 32 and 80 seconds and the 
order of blocks is counterbalanced across subjects. This design is modified from prior event-
related designs so as to yield a 61% improvement in design efficiency (calculated by 
FMRIB’s software library FSL), which we confirmed to lead to more extensive and more 
intense BOLD response. The data can be analyzed offline and used for experimental control 
variables. Next, two 6 minutes resting state runs will be collected.  During these runs, 
participants  will be asked to stare at a cross-hair on the screen. Finally, a diffusion tensor 
imaging (DTI) scan will be obtained over 5 minutes.
5. Participants will be then taken out of the scanner and given one oral dose of either 30 mg of 
Morphine, or 50 mg of Naltrexone or placebo. 60 minutes later, VS will be collected again 
and logged in to the VS sheet and participants will undergo another scanning session while 
receiving milkshake, sucrose or tasteless solutions as described in 3 and while at rest.  DTI 
and structural imaging will not be repeated. Blood pressure and heart rate will be 
continuously monitored during scanning using the Biopac system. The same procedure 
will be followed for the same participants in two subsequent visits (Day 4 and Day 5). The 
visits will be scheduled within a 
period spanning 4 weeks but no 
two-treatment 
days 
will 
be 
scheduled less than 48 hours 
apart. The overall design of the 
study will follow the illustration in 
Figure 1.  However, the order of 
the interventions (i.e. Morphine, 
Naltrexone or placebo) will be 
randomized. The scanning session 
after 
medication 
administration 
will last between 45-60 minutes.  
Participants vital signs and mental 
and neurological state will be monitored for an additional 2 hours post-scanning at an interval 
of one hour using the NIH Stroke Scale Neurological Assessment flow sheet (two 
assessments in total); after 2 hours, if participants mental and neurologic state and VS are 
stable they will be reminded about side-effects of morphine and naltrexone and released. 
Morphine sulfate half-life is 2-4 hours.  By the time our participants leave the MRRC one to 
two half-lives would have passed and the blood level of morphine would have dropped 2 to 4 
times relative to time at ingestion. 
B. Description of the open label arm
Figure 1.  Schematic illustration of study design; the order is 
just one example for one participants; the interventions will 
be randomized in a double blind protocol. 
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The same procedures described in A will be used to study 15 CBP patients using an 
open label design except when participants are taken to the scanner.  At that point both 
the experimenter and the participant will know that morphine 30 mg  is being 
administered. In addition, this arm of the study will have one arm only.
4. Genetic Testing   N/A 
A. Describe
i.
the types of future research to be conducted using the materials, specifying if 
immortalization of cell lines, whole exome or genome sequencing, genome wide 
association studies, or animal studies are planned.
No future research is planned with the materials. We will determine the presence or 
absence of candidate opiate activity-related genes after the subject has provided their 
saliva.
ii. the plan for the collection of material or the conditions under which material will 
be received
The Oragene-DNA Self-Collection Kit (vial format) will be used to collect DNA 
samples. This kit is an all-in-one system for the collection, preservation, and 
purification of DNA from saliva. The subjects will be asked to deliver the saliva in 
the container of the kit. After the delivery, the container will be capped which results 
in releasing DNA-preserving fluid that mixes with the saliva. This way, the DNA can 
be stored for long-term at room temperature. After collection, the DNA samples will 
be coded by a numeric code. This numeric code corresponds with the numeric code 
given to that particular subject in the study. The DNA samples will be analyzed in 
this lab using standard DNA procedures. Different sequence regions will be analyzed 
from each of the genomic DNA samples. The sequences will first be amplified using 
polymerase chain reaction (PCR) techniques, based on primer sequences specific for 
each sequence of interest. The amplified PCR products will then be digested with 
restriction enzymes as appropriate and analyzed using agarose gel electrophoresis. 
Images of each processed gel will be taken using a cooled-CCD camera system 
(ChemiDoc, Bio-Rad) and the presence or absence of a given allele will be 
determined based on the predicted sizes of the PCR products. 
iii. the types of information about the donor/individual contributors that will be 
entered into a database
No protected health information (PHI) will be kept with the DNA samples. Only 
authorized staff will have access to the password-protected file that links name and 
ID number on a secure server. The genetic data will be used in analyses with 
information participants provided during the previous behavioral and fMRI 
sessions, which includes demographic information, body mass index, dietary habits, 
ratings, and brain imaging data (but no PHI data). By linking these data, the genetic 
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information should provide insight into understanding differential brain response 
among individuals. 
iv. the methods to uphold confidentiality
The collected DNA samples will be stored at The John B. Pierce Laboratory. Only 
authorized study personnel may remove the samples for analysis. Data will be kept 
on the password-protected server for a period of seven years to ensure that the 
researchers have access to results. After seven years, the identifying data will be 
destroyed.
B. What are the conditions or procedures for sharing of materials and/or distributing for 
future research projects?
N/A . We do not plan to share of distribute these materials for future research 
projects.
C. Is widespread sharing of materials planned?
N/A
D. When and under what conditions will materials be stripped of all identifiers?
The materials are stripped of PHI after collection and coded with a subject ID 
number. After seven years, the identifying data will be destroyed. 
E. Can donor-subjects withdraw their materials at any time, and/or withdraw the identifiers 
that connect them to their materials?
i.
How will requests to withdraw materials be handled (e.g., material no longer 
identified: that is, anonymized) or material destroyed)?
Yes, subjects can withdraw their materials at any time by contacting the PI, a 
procedure described in the consent form. If a subject wished to withdraw their 
materials, we will locate the material by the subject ID by accessing the password 
protected file that links name and ID, and destroy the biological material and any 
paper or electronic record of their genetic information. The saliva sample will be 
destroyed and the raw data from these samples will be destroyed by soaking the 
sample in bleach. This will remove all DNA. We will also remove the subject from 
any analyses.
F. Describe the provisions for protection of participant privacy
No PHI will be kept with the DNA samples. Only authorized staff will have access to 
the password-protected file that links name and ID number on a secure server. 
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G. Describe the methods for the security of storage and sharing of materials 
Only authorized staff will have access to the password-protected file that links name 
and ID number on a secure server. Data will be kept on the password-protected 
server for a period of seven years to ensure that the researchers have access to 
results. After seven years, the data will be deleted by zeroing with software as in 
accordance with policies and procedures as determined by Yale University 
(procedures 1609 and 1610).
5. Subject Population: Provide a detailed description of the types of human subjects who will 
be recruited into this study.
The subjects will be healthy human adults, and human adults suffering from pain 
conditions such as low back pain, knee arthritis, or fibromyalgia with normal gustatory 
and olfactory function and no medical conditions that would preclude them from being 
tested in the MR scanner. These subjects will be recruited from the Yale University 
Community, including undergraduate students, graduate students, and staff, with an 
age range between 18 and 65 years. Women and minorities will be encouraged to 
participate in all proposed experiments. We will monitor the subject pool periodically 
to ensure appropriate representation of all ethnic backgrounds and both sexes. 
6. Subject classification: Check off all classifications of subjects that will be specifically 
recruited for enrollment in the research project. Will subjects who may require additional 
safeguards or other considerations be enrolled in the study? If so, identify the population of 
subjects requiring special safeguards and provide a justification for their involvement.
 Children
 Healthy 
Fetal material, placenta, or dead fetus
 Non-English Speaking
 Prisoners
 Economically disadvantaged persons
 Decisionally Impaired
 Employees
 Pregnant women and/or fetuses
 Yale Students 
Females of childbearing potential
NOTE: Is this research proposal designed to enroll children who are wards of the state as 
potential subjects? 
 Yes  
 No (If yes, see Instructions section VII #4 for further 
requirements)
7. Inclusion/Exclusion Criteria: What are the criteria used to determine subject inclusion or    
exclusion?
Inclusion criteria: 
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Healthy participants
Patients in pain: suffering from persistent pain more days than not, 3/10 in intensity on a 
numerical rating scale, for at least 6 weeks or more.
Exclusion criteria: Any DSM diagnosis, diabetes, food allergies, lactose intolerance, 
participants seeking to quit smoking or to lose weight, participants on any psychotropic 
medication including opiate based analgesics (e.g. oxycodone, methadone, suboxone), 
pregnant or nursing women, pacemaker or other implanted electrical devices. Participants 
with a past history of head trauma or seizures will be excluded.  Any past history of illegal 
drug or alcohol misuse will be an exclusion criterion.
8. How will eligibility be determined, and by whom? 
Eligibility will be determined by the research coordinator upon initial telephone contact 
using a screening form (see attached phone screening form). The form asks general 
information questions (date of birth, handedness, native language, etc.) and queries the 
participants about their health and any history of conditions known to affect cognitive 
functioning (e.g. stroke, medications, head trauma), or any conditions that could 
compromise the safety of conducting an MRI scan (e.g. claustrophobia, metal in the 
body, pacemaker). A more lengthy MRI safety screening form will be administered 
when the participant arrives for the scanning session (see attached MRI screening 
form) at the Magnetic Resonance Research Center in the Congress Avenue building of 
Yale School of Medicine.  We do not wish to study females who are or may be pregnant.  
Therefore, as part of our MRI safety screening protocol, all females of childbearing 
potential will be given a urine pregnancy test prior to scanning.  Results of the 
pregnancy test will be given to them only and will remain confidential.  If the results 
indicate a subject is pregnant she will not participate in the fMRI scan, and will be 
excluded from the study.
9. Risks: Describe the reasonably foreseeable risks, including risks to subject privacy, 
discomforts, or inconveniences associated with subjects participating in the research. 
Risk involved with the questionnaires 
It is possible that interviews may cause distress or concern to the participants. One potential 
risk to participants is that it may be distressing to disclose information about psychiatric 
difficulties such as previous history of substance misuse. In our estimation, there is a low risk 
of this possibility and the effects would probably be short lived. We have conducted several 
hundred of these interviews with no adverse effects. It is possible that subjects may become 
frustrated with some of the impulsivity or cognitive assessments. We have conducted 
hundreds of similar cognitive assessments and have had no adverse outcomes. 
Risks involved with the mock fMRI scanner
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It is also possible that subjects report feeling uncomfortable in the mock scanner, either 
because they feel claustrophobic or because they do not like swallowing in a supine position. 
Subjects will be instructed to tell the experimenter if they feel any discomfort with the 
procedure so that the session can be terminated. We have conducted hundreds of fMRI 
training sessions. Approximately 1 in 15 subjects report some discomfort with this procedure 
and the sessions are terminated. We have had no adverse events.
Risks associated with one dose of oral 30 mg Morphine:
Morphine is an opiate agonist and has been used clinically for centuries. There is no clear 
compelling evidence of long-term toxicity from using one dose of 30 mg oral morphine. 
However, there are acute medical and neuropsychiatric sequelae that deserve special 
consideration.  Acute administration can lead to dizziness, somonolence, dysphoria, altered 
mental status, euphoria, edema, diaphoresis, headache, parasthesias, flushing, respiratory 
depression, hypotension, rash or pruritis, nausea, constipation and vomiting.  Very serious 
but extremely rare side effects include anaphylaxis, apnea, severe bradycardia or 
hypotension, or shock.
Risks associated with one dose of oral 50 mg Naltrexone:
Naltrexone is an opiate antagonist and has been used clinically for several decades. There are 
no long-term side effects of one dose of oral naltrexone; in fact, naltrexone is prescribed 
daily for alcohol misuse disorder to prevent relapse into drinking. Acute administration can 
be associated with insomnia, dizziness, fatigue, somnolence, headache, anxiety, abdominal 
pain, nausea, vomiting.  Extremely rare side effects include hypersensitivity reaction and 
hepatotoxicity. 
Risks involved with MRI
MRI and MRS are considered to be among the safest ways to examine the human body.  
They use magnetism and radio waves, not x-rays, to measure chemicals and take pictures of 
various parts of the body.  The United States Food and Drug Administration (FDA) has set 
guidelines for magnet strength and exposure to radio waves, and we carefully observe those 
guidelines.  For subjects’ exposure in this study, no bad effects have been seen.  This study 
has no painful parts.  Subjects will be watched closely throughout the study.  Some people 
may feel uncomfortable or anxious during the MRI or MRS.  If this happens to a subject, 
they may ask to stop the study at any time and we will take him/her out of the MR scanner.  
On rare occasions, some people might feel dizzy, get an upset stomach, have a metallic taste 
or feel tingling sensations or muscle twitches.  These sensations usually go away quickly but 
subjects should tell the research staff if they have them.  
MRI and MRS pose some risks for certain people.  If subjects have a pacemaker or some 
metal objects inside their body, they may not be in this study because the strong magnets in 
the MR scanner might harm them.  Another risk is a metallic object flying through the air 
toward the magnet and hitting them.  To reduce this risk we require that all people involved 
with the study remove all metal from their clothing and all metal objects from their pockets.  
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Nothing metal can be brought into the magnet room at any time.  Also, once a subject is in 
the magnet, the door to the room will be closed so that no one from outside accidentally goes 
near the magnet.
We want subjects to read the questions on the MR Safety Questionnaire and answer them 
very carefully.  Those questions are for their safety.  Subjects should take a moment to be 
sure that they have read the MR safety sheet and be sure to tell us any information they think 
might is important.  Even if they think that it is probably okay, we would rather have them 
ask us to make sure.
This MR study is for research purposes only and is not in any way a clinical scan to diagnose 
diseases for subjects.  The scans in this study are not designed for diagnosis.  The primary 
investigator, the lab, the MR technologist, and the Magnetic Resonance Research Center are 
not qualified to interpret the MR scans and cannot give subjects or their doctor a diagnostic 
evaluation of the images.  If we see something on their scan that might be medically 
significant, we will ask a radiologist or another physician to review the relevant images.  If 
that person recommends that the subject should seek medical advice, then the primary 
investigator or consulting physician will contact the subject, talk with them about the 
situation, and recommend that they seek medical advice as a precautionary measure.  At that 
point, the decision to seek advice or treatment is completely up to the subject and their 
doctor.  If the subject’s doctor wants to pursue additional MR images, the research scans 
from this study will not be available, and new scans that are appropriate for medical 
diagnosis will need to be done.  The researchers for this project, the consulting physician, the 
Magnetic Resonance Research Center, and Yale University are not responsible for any exam 
or treatment that the subject receives based on these findings.
Risks associated with the physiological recordings of respiration, heart rate, swallowing and 
galvanic skin response in the MRI environment.:
There are no known risks associated with these recordings. However, should the subjects 
feel anxious or uncomfortable with the any aspect of the recordings we will simply acquire 
the fMRI scan without them.
Risks-associated with the BodPod measurement:
There are no known risks associated with the BodPod measurement. However, some people 
may feel uncomfortable or anxious in the enclosed chamber of the BodPod. After each of the 
three 50-second measurements the experimenter will open the door. The experimenter can 
see the subject at all times in the BodPod and will show you the alarm button inside the 
BodPod that will interrupt the measurement if they feel anxious.
Risks associated with the physiological recordings in the MRI environment:
There are no known risks associated with these recordings. However, should the subjects 
feel anxious or uncomfortable with the any aspect of the recordings we will simply acquire 
the fMRI scan without them.
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Risks involved with consumption of stimuli:
There are no known risks associated with consumption of any of the odors or liquids that 
subjects will encounter.  All are commercially available products that subjects will have 
likely encountered before.  Subjects with food allergies or sensitivities (for example nuts, 
lactose, artificial sweeteners) will be excluded.  
Risks involved with blood draws:
Potential risks associated with blood sampling include infection from failure to observe proper 
sterile conditions, and hematoma from careless technique. The latter may be associated with 
some discomfort, but presents very little danger to the subject’s welfare. In any case, a skilled 
phlebotomist will perform all blood draws.
Risks involved with pregnancy:
MR scans, and a restricted diet could be damaging for a developing fetus. Therefore, 
pregnant women will be excluded.
Risks for toxicology screenings:
Breath screening and urine collections are performed primarily as safeguards to 
contamination of data and should add no risks other than those normally associated with 
these procedures.
Risks for saliva sample collection and genotyping:
There is a slight risk of genetic information being used in inappropriate ways (e.g. to deny 
health insurance due to genotype).
10. Minimizing Risks: Describe the manner in which the above-mentioned risks will be 
minimized.
All researchers and research assistants involved in the study have taken the Human 
Investigations Training Course either on-line (through the NIH) or in person through the 
Yale University School of Medicine. All clinical procedures are performed the John B Pierce 
Laboratory by trained medical and scientific staff. Subjects may become anxious or fatigued 
during any of the procedures. They will be informed at the outset of the study that, should 
they experience undue anxiety or discomfort from the procedures, they are free to terminate 
the study at any time. Trained staff members will be working with the subjects throughout 
the study and will take appropriate steps to minimize anxiety and fatigue. We will attempt to 
minimize any discomfort associated with the procedures by informing the subject about what 
to expect prior to participation. Participants will be told that they are free to not respond or to 
terminate involvement at any time with no adverse consequences. All lab assessors are 
extensively trained on how to conduct assessments. Dr. Geha will also closely supervise all 
assessors.
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Minimizing risk involved with administration of one oral dose of Morphine and Naltrexone
We will minimize the acute risk of administration of oral 30 mg Morphine or 50 mg of 
Naltrexone by carefully monitoring vital signs and mental status using neuro-checks every 60 
minutes after the administration. In addition, the study physician Dr. Paul Geha will always 
be present during the whole duration of the visit when either of these drugs is administered.
Minimizing risk involved with the questionnaires:
Should a subject meet diagnostic criteria for any psychiatric disorder Dr. Geha will refer 
them for treatment. If a participant appears to be distressed or fatigued during assessments, 
the assessor will halt the procedure and take a break. The session will only recommence 
when and if the participant reports feeling capable of continuing
Minimizing risks involved with the mock fMRI scanner
We will attempt to minimize any discomfort associated with the mock fMRI scanner by 
informing the subject about what to expect prior to participation and explaining to them the 
equipment, how it works, which parts are replaced for every subject and how we clean any 
components that are not. Subjects will be instructed to tell the experimenter if they feel any 
discomfort with the procedure so that the session can be terminated.
Minimizing risks involved with MRI
During the fMRI scans, the participants will be monitored for anxiety or related concerns by 
research personnel associated with the project. Participants and investigators will be 
screened for metallic objects prior to entering the scan room. Prior to inclusion in the study, 
the presence of potential MRI risks, such as pacemakers, surgical clips, or metallic devices 
will be excluded by medical and surgical history administered during screening. All subjects 
will wear foam earplugs and sound-reducing headphones to reduce risk of hearing damage 
due to the loud noise of the scanner. The minor risk of discomfort due to lying still for 60 
minutes will be minimized by providing custom pads and pillows designed to make the 
participants as comfortable as possible. Participants will communicate with the MR 
technologist and research assistant via an intercom system and may trigger and audible 
alarm at any time to stop the MRI session if he or she is uncomfortable or anxious. In 
addition, all imaging center staff, students, post-docs and research assistants will participate 
in safety training annually. Finally, all subjects are familiarized with MR procedures during 
the training session in the mock scanner to ensure that subjects that are schedule for the MR 
scan are comfortable with the procedures.
Minimizing risks related to pregnancy
To minimize risks related to pregnancy, we inform the subject that if they should become 
pregnant, they should report this to their health care professional, physician and to us 
immediately. If this happens during the study, the subject will stop his/her participation. We 
perform pregnancy tests along with toxicology tests during each assessment and intake.
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Minimizing risks associated with the BodPod
The experimenter can see the subject at all times in the BodPod and will show them the 
alarm button inside the BodPod that will interrupt the measurement if they feel anxious.
Minimizing risks for toxicology screenings:
Every subject will use a new separately wrapped mouthpiece that will be attached to the 
breathalyzer. Bottles containing subject's urine specimens will be not be labeled and will be 
appropriately discarded in a biohazard container after instant testing. This information is not 
recorded.
Minimizing risks for saliva sample collection and genotyping:
No protected health information (PHI) will be kept with the DNA samples. Only authorized 
staff will have access to the password protected file that links name and ID number on a 
secure server.  Identifying data will be destroyed after 7 years. Genetic information will also 
not be disclosed to participants, physicians in order to maintain confidentiality and limit the 
possible misuse of genetic information. 
11. Data and Safety Monitoring Plan: Include an appropriate Data and Safety Monitoring Plan 
(DSMP) based on the investigator’s risk assessment stated below. (Note: the HIC will make 
the final determination of the risk to subjects.) For more information, see the Instructions, 
page 24.
a.
What is the investigator’s assessment of the overall risk level for subjects 
participating in this study? 
The  investigator’s assessment of the overall risk for subjects participating in this 
study is moderate.
b. If children are involved, what is the investigator’s assessment of the overall risk level 
for the children participating in this study? 
Not Applicable.
c.
Include an appropriate Data and Safety Monitoring Plan. Examples of DSMPs are  
 available here http://www.yale.edu/hrpp/forms-templates/biomedical.html  for
i. Minimal risk
ii. Greater than minimal
d. For multi-site studies for which the Yale PI serves as the lead investigator:
i. How will adverse events and unanticipated problems involving risks to subjects or 
others be reported, reviewed and managed?
ii. What provisions are in place for management of interim results?
iii. What will the multi-site process be for protocol modifications?
Moderate Risk DSMP
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1. Personnel responsible for the safety review and its frequency:
The principal investigator, Dr. Paul Geha,  will be responsible for monitoring the data, assuring 
protocol compliance, and conducting the safety reviews at the specified frequency, which must 
be conducted at a minimum of every 6 months (including when reapproval of the protocol is 
sought).  During the review process, the principal investigator (monitor) will evaluate whether 
the study should continue unchanged, require modification/amendment, or close to enrollment. 
Either the principal investigator, or the IRB have the authority to stop or suspend the study or 
require modifications.
The risks associated with the current study are deemed greater than minimal for the 
following reasons: (choose those that apply)
1. We do not view the risks associated with morphine or naltrexone as minimal risk.
2. We do not view the risks associated with the combined use of morphine or naltrexone 
and fMRI as minimal risks.
3. Given the now established safety and validity of the current _________ in our prior work, 
we do not view the proposed studies as high risk.
4. Given our experience with the combined co-administration_________, we do not view 
the proposed studies as high risk.
Although we have assessed the proposed study as one of greater moderate risk, the potential 
exists for anticipated and/or unanticipated adverse events, serious or otherwise, to occur since it 
is not possible to predict with certainty the absolute risk in any given individual or in advance of 
first-hand experience with the proposed study methods. Therefore, we provide a plan for 
monitoring the data and safety of the proposed study as follows:
3. Attribution of Adverse Events:
Adverse events will be monitored for each subject participating in the study and attributed to the 
study procedures / design by the principal investigator, Dr. Paul Geha,  according to the 
following categories:
a.) Definite: Adverse event is clearly related to investigational procedures(s)/agent(s).
b.) Probable: Adverse event is likely related to investigational procedures(s)/agent(s).
c.) Possible: Adverse event may be related to investigational procedures(s)/agent(s).
d.) Unlikely: Adverse event is likely not to be related to the investigational 
procedures(s)/agent(s).
e.) Unrelated: Adverse event is clearly not related to investigational procedures(s)/agent(s).
4. Plan for Grading Adverse Events:
The following scale will be used in grading the severity of adverse events noted during the study:
1. Mild adverse event
2. Moderate adverse event
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3. Severe 
5. Plan for Determining Seriousness of Adverse Events:
Serious Adverse Events:
In addition to grading the adverse event, the PI will determine whether the adverse event meets 
the criteria for a Serious Adverse Event (SAE).  An adverse event is considered serious if it 
results in any of the following outcomes:
1. Death;
2. A life-threatening experience in-patient hospitalization or prolongation of existing 
hospitalization; 
3. A persistent or significant disability or incapacity; 
4. A congenital anomaly or birth defect; OR
5. Any other adverse event that, based upon appropriate medical judgment, may jeopardize 
the subject’s health and may require medical or surgical intervention to prevent one of 
the other outcomes listed in this definition. 
An adverse event may be graded as severe but still not meet the criteria for a Serious Adverse 
Event.  Similarly, an adverse event may be graded as moderate but still meet the criteria for an 
SAE.  It is important for the PI to consider the grade of the event as well as its “seriousness” 
when determining whether reporting to the IRB is necessary.
Plan for reporting UPIRSOs (including Adverse Events) to the IRB
The principal investigator will report the following types of events to the IRB: 
Any incident, experience or outcome that meets ALL 3 of the following criteria:
1. Is unexpected (in terms of nature, specificity, severity, or frequency) given (a) the 
research procedures described in the protocol-related documents, such as the IRB-
approved protocol and informed consent document and (b) the characteristics of the 
subject population being studied; AND 
2. Is 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
3. Suggests that the research places subjects or others at greater risk of harm (including 
physical, psychological, economic, legal, or social harm) than was previously known 
or recognized.
Unanticipated Problems Involving Risks to Subjects or Others (UPIRSOs) may be medical or 
non-medical in nature, and include – but are not limited to – serious, unexpected, and related 
adverse events and unanticipated adverse device effects.  Please note that adverse events are 
reportable to the IRB as UPIRSOs only if they meet all 3 criteria listed above.
These UPIRSOs/SAEs will be reported to the IRB in accordance with IRB Policy 710, using the 
appropriate forms found on the website. All related events involving risk but not meeting the 
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prompt reporting requirements described in IRB Policy 710 should be reported to the IRB in 
summary form at the time of continuing review. If appropriate, such summary may be a simple 
brief statement that events have occurred at the expected frequency and level of severity as 
previously documented.  In lieu of a summary of external events, a current DSMB report can be 
submitted for research studies that are subject to oversight by a DSMB (or other monitoring 
entity that is monitoring the study on behalf of an industry sponsor).
7. Plan for reporting adverse events to co-investigators on the study, as appropriate the 
protocol’s research monitor(s), e.g., industrial sponsor, Yale Cancer Center Data and 
Safety Monitoring Committee (DSMC), Protocol Review Committee (PRC), DSMBs, study 
sponsors, funding and regulatory agencies, and regulatory and decision-making bodies.
For the current study, the following individuals, funding, and/or regulatory agencies will be 
notified (choose those that apply):
□ All Co-Investigators listed on the protocol.
□ National Institutes of Health
The principal investigator , Dr. Paul Geha, will conduct a review of all adverse events upon 
completion of every study subject. The principal investigator will evaluate the frequency and 
severity of the adverse events and determine if modifications to the protocol or consent form are 
required.
12. Statistical Considerations: Describe the statistical analyses that support the study design. 
fMRI Data Analysis: The following measures will be derived from brain data: (1) parameter 
estimates(PE) for milkshake (MS) minus Tls (tasteless) (MS-Tls) will be defined at the 
single subject level using general linear model (GLM), implemented in FSL toolbox55;whole 
brain connectivity of Blood Oxygen Level Dependent (BOLD) signal, using both MS runs or 
resting state runs, will be calculated between each voxel, or region of interest (ROI), and 
every other voxel in the brain to obtain (2) functional connectivity FC of specific ROIs  or  
(3) degree maps (DM).  FC is a measure of the strength of connectivity between an ROI and 
the rest of the brain; degree D is calculated as the total number of connections above a 
specific correlation threshold between a voxel and all the other voxels in the brain; we will 
study D over a range of thresholds 0.25 < r <0.65 56.  DM identifies brain hubs (with high D) 
and therefore allows between groups comparison in the most densely connected areas 57,58.
The design is a within subject repeated measures design with treatment  (Morphine, 
Naltrexone and Placebo) being the repeated measure and groups (healthy control vs. pain 
patients) as a factor.  We will use repeated measures ANOVA to find differences in brain 
response (i.e. (MS-Tls) or D or FC) and psychophysical ratings of milkshake. The repeated 
measures design is a powerful one because it does not suffer from between subject 
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variability.  According to the preliminary data we expect to see decreased response to MS in 
opiate treated back pain patients and decreased D and FC. 
SECTION VI: RESEARCH INVOLVING DRUGS, BIOLOGICS, RADIOTRACERS, PLACEBOS AND 
DEVICES
If this section (or one of its parts, A or B) is not applicable, state N/A and delete the rest of the 
section.
A.  DRUGS, BIOLOGICS and RADIOTRACERS
1. Identification of Drug, Biologic or Radiotracer: What is (are) the name(s) of the drug(s) 
biologic(s)  or radiotracer(s) being used? Identify whether FDA approval has been granted and for 
what indication(s). 

Morphine has U.S.  Food and Drug Administration (USFDA) approval for relief of 
moderate to severe acute and chronic pain for which use of an opioid analgesic is 
appropriate.

Naltrexone has USFDA approval for treatment of alcohol dependence and blockade of the 
effects of exogenously administered opioids.
All protocols, which utilize a drug, biologic, or radiotracer not approved by, but regulated by, the 
FDA, or a radiotracer regulated by the RDRC, must provide the following information:  
a. What is the Investigational New Drug (IND) number assigned by the FDA?
b. Who holds the IND? 
c. All protocols, which utilize a radiotracer not approved by, but regulated by the FDA, must 
provide the IND number: _______________
Alternatively, use of the investigational radiotracer may be under RDRC/RSC oversight: (check 
if appropriate)_____________
For all investigational radiotracers, attach a copy of the RDRC/RSC application (for 
radioisotopes used in the PET Center, PET Center personnel may complete this step)
Go to http://rsc.med.yale.edu/login.asp?url=myApps.asp.  When you have logged in, complete 
the application and attach a copy to this submission.     
Alternatively, an exemption from IND filing requirements may be sought for a clinical
 investigation of a drug product that is lawfully marketed in the United States. If there is no IND and
 an exemption is being sought, review the following categories and complete the category that applies
 (and delete the inapplicable categories):
Exempt Category 1
The clinical investigation of a drug product that is lawfully marketed in the United States can be
exempt from IND regulations if all of the following are yes:
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i.   The intention of the investigation is NOT to report to the FDA as a well-controlled study in support
     of a new indication for use or to be used to support any other significant change in the labeling for
     the drug.  
 Yes  
 No
ii. The drug that is undergoing investigation is lawfully marketed as a prescription drug product, and
      the intention of the investigation is NOT to support a significant change in the advertising for the
      product. 
 Yes  
 No
iii.  The investigation does NOT involve a route of administration or dosage level or use in populations
      or other factor that significantly increases the risks (or decreases the acceptability of the risks)   
      associated with the use of the drug product. 
 Yes  
 No
iv. The investigation will be conducted in compliance with the requirements for institutional (HIC)   
      review and with the requirements for informed consent of the FDA regulations (21 CFR Part 50  
and 21 CFR Part 56). 
 Yes  
 No
v.   The investigation will be conducted in compliance with the requirements regarding promotion and 
charging for investigational drugs. 
 Yes  
 No
Exempt Category 2 (all items i, ii, and iii must be checked to grant a category 2 exemption)
 i. The clinical investigation is for an in vitro diagnostic biological product that involves one or
more of the following (check all that apply):
 Blood grouping serum
 Reagent red blood cells 
 Anti-human globulin
 ii. The diagnostic test is intended to be used in a diagnostic procedure that confirms the
diagnosis made by another, medically established, diagnostic product or procedure; and
 iii. The diagnostic test is shipped in compliance with 21 CFR §312.160.
Exempt Category 3
 The drug is intended solely for tests in vitro or in laboratory research animals if shipped in 
accordance with 21 CFR 312.60
Exempt Category 4
 A clinical investigation involving use of a placebo if the investigation does not otherwise 
require submission of an IND.
2. Background Information: Provide a description of previous human use, known risks, and data 
addressing dosage(s), interval(s), route(s) of administration, and any other factors that might 
influence risks. If this is the first time this drug is being administered to humans, include relevant 
data on animal models. 
Oral Morphine is prescribed to millions of patients suffering from pain; it is estimated that 
the number of prescription filled for opioid medications exceeded 256 millions in 2009 in the 
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US59,60.  The starting dose is typically 10 to 30 mg every 4 hours as needed.  Patients with 
prior opioid exposure may require higher initial doses. For the purpose of the current 
proposal we will administer only one dose of 30 mg morphine. Therefore, the risks 
associated with chronic use of morphine are largely minimized by our protocol.  Oral 
Morphine has a wide margin of safety at 2-3 times of the “effective dose”. In addition, there is 
no evidence of long-term toxicity associated with the intake of one dose of Morphine. Several 
human imaging studies safely administered acute61-72 or chronic 73 opiate medications, 
including oral morphine, via the oral or the parenteral route.  Morphine side effects are dose 
and route of administration dependent; the most frequent side effects (> 10%) described are:

Cardiovascular: Oxygen saturation decreased

Central nervous system: Drowsiness (9% to >10%), headache (<2% to >10%)

Gastrointestinal: Constipation (9% to >10%), nausea (7% to >10%), vomiting (2% 
to >10%)

Genitourinary: Urinary retention (<2% to 16%; primarily in males; may be 
prolonged, up to 20 hours, following epidural or intrathecal use)

Hypersensitivity: Histamine release

Neuromuscular & skeletal: Weakness
Side effects in 1% to 10%:

Cardiovascular: Peripheral edema (3% to 10%), chest pain (2% to <3%), atrial 
fibrillation (<2% to <3%), bradycardia (<2%), edema (<2%), facial flushing (<2%), 
flushing (<2%), hypertension (<2%), hypotension (<2%), palpitations (<2%), 
syncope (<2%), tachycardia (<2%), vasodilatation (<2%), circulatory depression, 
orthostatic hypotension, presyncope, shock

Central nervous system: Depression (5% to 10%), insomnia (<2% to 10%), 
paresthesia (<2% to 10%), dizziness (6%), anxiety (<2% to 6%), abnormality in 
thinking (<2% to <5%), confusion (<2% to <5%), convulsions (<5%), pain (3%), 
agitation (<2%), amnesia (<2%), apathy (<2%), ataxia (<2%), chills (<2%), 
decreased cough reflex (<2%), dream abnormalities (<2%), euphoria (<2%), 
hallucination (<2%), hypoesthesia (<2%), lack of concentration (<2%), lethargy 
(<2%), malaise (<2%), myoclonus (<2%), seizure (<2%), slurred speech (<2%), 
vertigo (<2%), voice disorder (<2%), withdrawal syndrome (<2%), abnormal gait, 
apprehension, coma, delirium, drug dependence, dysphoria, false sense of well-
being, feeling abnormal, mood changes, nervousness, restlessness, rigors, sedation

Dermatologic: Diaphoresis (5% to 10%), skin rash (3% to 10%), decubitus ulcer 
(<2%), pallor (<2%), pruritus (<2%, may be dose related), urticaria, xeroderma

Endocrine & metabolic: Gynecomastia (<2% to <3%), amenorrhea (<2%), 
decreased libido (<2%), hyponatremia (<2%), antidiuretic effect, hypogonadism, 
hypokalemia, increased release of antidiuretic hormone, increased thirst, weight loss

Gastrointestinal: Abdominal pain (5% to 10%), diarrhea (5% to 10%), anorexia (3% 
to 10%), xerostomia (3% to 10%), biliary colic (<2%), delayed gastric emptying 
(<2%), dyspepsia (<2%), dysphagia (<2%), gastric atony (<2%), gastroesophageal 
reflux disease (<2%), hiccups (<2%), abdominal distension, dysgeusia, flatulence, 
gastroenteritis, GI irritation, paralytic ileus, rectal disease
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
Genitourinary: Urinary tract infection (5% to 10%), impotence (<2%), prolonged 
labor (<2%), urinary hesitancy (<2%), urine abnormality (<2%), abnormal 
ejaculation, bladder spasm, decreased urine output, dysuria, hypogonadism, oliguria

Hematologic & oncologic: Anemia (2% to <5%), thrombocytopenia (<2% to <5%), 
leukopenia (2%), hematocrit decreased

Hepatic: Increased liver function enzymes

Hypersensitivity: Hypersensitivity reaction

Infection: Infection

Local: Local irritation

Neuromuscular & skeletal: Back pain (<2% to 10%), asthenia (2%), tremor (2%), 
arthralgia (<2%), bone pain (<2%), foot-drop (<2%), decreased bone mineral 
density, muscle rigidity, muscle twitching

Ophthalmic: Amblyopia (<2%), blurred vision (<2%), conjunctivitis (<2%), diplopia 
(<2%), miosis (<2%), nystagmus (<2%), eye pain, visual disturbance

Respiratory: Dyspnea (3% to 10%), flu-like symptoms (<2% to 10%), 
hypoventilation (<5%), asthma (<2%), atelectasis (<2%), hypoxia (<2%), 
pulmonary edema (noncardiogenic, <2%), respiratory depression (<2%), respiratory 
insufficiency (<2%), rhinitis (<2%), hypercapnia

Miscellaneous: Accidental injury (2% to 10%), fever (2% to 10%)
Side effects at < 1%

<1% (Limited to important or life-threatening): Anaphylaxis, apnea, biliary tract 
spasm, bronchospasm, decreased cough reflex, dehydration, disorientation, 
disruption of body temperature regulation, genitourinary tract spasm, hemorrhagic 
urticaria, hyperalgesia, hypertonia, increased intracranial pressure, intestinal 
obstruction, laryngospasm, menstrual irregularities, myoclonus, paradoxical central 
nervous system stimulation, sepsis, toxic psychoses
Oral Morphine is contraindicated in somebody who has bowel obstruction.
Oral Naltrexone: Oral Naltrexone is prescribed for alcohol and opiate dependence; it is 
estimated that 221 million prescriptions of Naltrexone were dispensed in 2007 74.  The starting 
dose is 50 mg daily. Naltrexone has a wide margin of safety. Naltrexone has a low incidence of 
common adverse events75. Naltrexone’s FDA-approved label includes a black-box warning 
regarding hepatotoxicity, although these reversible effects tend to be associated with much 
higher doses than those used in routine clinical practice (e.g., 300 mg/day or more) and tend to 
occur only after a patient is on these high doses for extended periods.  For the purpose of our 
current protocol we will use one 50 mg dose one time only. In addition, there is no evidence of 
long-term toxicity associated with the intake of one dose of Naltrexone.  Naltrexone side effects 
occurring at > 10% rate are reported for combined oral and injectable form; however, as 
mentioned above oral Naltrexone has a low risk of side effects. 
>10%:
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
Cardiovascular: Syncope (13%)

Central nervous system: Headache (3% to 25%), insomnia (3% to 14%), dizziness 
(4% to 13%), anxiety (2% to 12%), decreased energy (>10%), nervousness (4% to 
>10%)

Gastrointestinal: Nausea (10% to 33%), vomiting (3% to 14%), appetite decreased 
(14%), diarrhea (13%), abdominal pain (11%), abdominal cramping

Hepatic: ALT increased (13%)

Neuromuscular & skeletal: CPK increased (11% to 39%), arthralgia (12%), myalgia 
(>10%)

Respiratory: Pharyngitis (7% to 11%)
1% to 10%:

Cardiovascular: Hypertension (5%)

Central nervous system: Suicidal ideation (≤10%), depression (8%), somnolence 
(2% to 4%), fatigue (4%), chills, energy increased, feeling down, irritability

Dermatologic: Skin rash (6% to 10%)

Endocrine & metabolic: Increased thirst, polydipsia

Gastrointestinal: Dry mouth (5%), toothache (4%), constipation

Genitourinary: Delayed ejaculation (<10%), impotency (<10%)

Hepatic: AST increased (2% to 10%), GGT increased (7%)

Neuromuscular & skeletal: Muscle cramps (8%), back pain (6%)

Miscellaneous: Influenza (5%)
3. Source: a) Identify the source of the drug or biologic to be used. 
b) Is the drug provided free of charge to subjects? 
 Yes  
 No
    If yes, by whom? 
4. Storage, Preparation and Use: Describe the method of storage, preparation, stability information, 
and for parenteral products, method of sterilization and method of testing sterility and 
pyrogenicity. 
Check applicable Investigational Drug Service utilized:
     
   YNHH IDS                                                                      
   Yale Cancer Center 
     
   CMHC Pharmacy                                                          
  West Haven VA
     
   PET Center                                                     
    None      
     
    Other: 
Note: If the YNHH IDS (or comparable service at CMHC or WHVA) will not be utilized, explain in 
detail how the PI will oversee these aspects of drug accountability, storage, and preparation.  
  
5. Use of Placebo: 
 Not applicable to this research project
If use of a placebo is planned, provide a justification which addresses the following:
1.
Describe the safety and efficacy of other available therapies. If there are no other
available therapies, state this.
There are no other therapies
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b. State the maximum total length of time a participant may receive placebo while on the 
study. 
One dose one time only
c.   Address the greatest potential harm that may come to a participant as a result of  receiving    
  
   placebo. 
The potential harm is an allergic reaction to one dose of placebo which is extremely unlikely
c.
Describe the procedures that are in place to safeguard participants receiving placebo. 
The protocol is a safeguard to receiving placebo since we are giving one dose only and 
not withholding any other treatment
6. Use of Controlled Substances:
Will this research project involve the use of controlled substances in human subjects?
 Yes  
 No See HIC Application Instructions to view controlled substance listings. 
If yes, is the use of the controlled substance considered:
 Therapeutic: The use of the controlled substance, within the context of the research, has the 
potential to benefit the research participant.
 Non-Therapeutic: Note, the use of a controlled substance in a non-therapeutic research study 
involving human subjects may require that the investigator obtain a Laboratory Research License. 
Examples include controlled substances used for basic imaging, observation or biochemical 
studies or other non-therapeutic purposes. See Instructions for further information.
The use of controlled substances in this protocol will follow the Yale Office of Environmental 
Health Policy for controlled substance according to the following point:

The controlled medication(s) will be ordered from the Yale New Haven Hospital 
pharmacy and delivered, used and destroyed on the same day; 

No storage of controlled medications will occur overnight in any research location; 

Only staff members listed on the protocol will sign for and take possession of the 
controlled medication(s);

If the medication(s) are not going to be administered immediately to the patient, the 
medication(s) will be stored in a lockable, secured device within John B. Pierce Lab

If the controlled medication is not fully used after the procedure, two staff members listed 
on the protocol (not the patient) will destroy the medication(s) and the destruction paperwork 
will include the following:  prescription number, pharmacy name, medication name, strength, 
quantity destroyed and signature of both parties that destroyed the medication(s) 

The study medications will be ordered through the YNHH IDS and each research subject 
will  have a YNHH Medical Record.  We have registered the study with Yale Center for Clinicial 
Investigation (YCCI).
7. Continuation of Drug Therapy After Study Closure  
 Not applicable to this project
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Are subjects provided the opportunity to continue to receive the study drug(s) after the study has 
ended?
 
 Yes   If yes, describe the conditions under which continued access to study drug(s) may apply 
as well as conditions for termination of such access. 
 
 No    If no, explain why this is acceptable. 
The drug administration is not intended to study treatment effects but the effects on brain activity.
B.  DEVICES
1.      Are there any investigational devices used or investigational procedures performed at Yale-
New Haven Hospital (YNHH) (e.g., in the YNHH Operating Room or YNHH Heart and 
Vascular Center)?  ☐Yes   ☒No    If Yes, please be aware of the following requirements:
a.       A YNHH New Product/Trial Request Form must be completed via EPIC: Pull down the 
Tools tab in the EPIC Banner, Click on Lawson, Click on “Add new” under the New 
Technology Request Summary and fill out the forms requested including the “Initial 
Request Form,” “Clinical Evidence Summary, “ and attach any other pertinent 
documents. Then select “save and submit” to submit your request; and
d. Your request must be reviewed and approved in writing by the appropriate YNHH 
committee before patients/subjects may be scheduled to receive the investigational device 
or investigational procedure.
2. What is the name of the device to be studied in this protocol?
Has this device been FDA approved? 
 Yes  
 No
If yes, state for what indication.
3. Background Information: Provide a description of previous human use, known risks, and 
any other factors that might influence risks. If this is the first time this device is being used in 
humans, include relevant data on animal models. 
4. Source: 
a) Identify the source of the device to be used. 
b) Is the device provided free of charge to subjects? 
 Yes  
 No
5. What is the PI’s assessment of risk level (significant or non-significant) associated with the 
use of the device? 
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 Significant Risk (SR) Device Study: A study of a device that presents a potential for serious 
risk to the health, safety, or welfare of a participant and 1) is intended as an implant; 2) is used in 
supporting or sustaining human life; or otherwise prevents impairment of human health; 3) is of 
substantial importance in diagnosing, curing, mitigating or treating disease, or otherwise prevents 
impairment of human health; or 4) otherwise presents a potential for serious risk to the health, 
safety, or welfare of a participant.   
Significant Risk Devices require an Investigational Device Exemption (IDE) issued by the FDA.
What is the IDE number assigned by the FDA? 
Did the FDA approve this IDE as Category A (experimental/investigational) or as Category B 
(non-experimental/investigational)?
Who holds the IDE?
 Non-Significant Risk (NSR) Device Study: A study of a device that does not meet the   
definition for a significant risk device and does not present a potential for serious risk to the health, 
safety, or welfare of participants.  Note that if the HIC concurs with this determination, an IDE is 
not required.
6.  Abbreviated IDE or Exempt IDE: There are abbreviated requirements for an IDE and 
there also are exemptions to the requirement for an IDE.  See the criteria in the HIC 
Application Instructions, Section VI.B.4 at 
http://www.yale.edu/hrpp/resources/docs/100FR1aHICProtocol_Application_Instructions5-
25-11.pdf to determine if these pertain to this study.
  
 Abbreviated IDE or Exempt IDE – If criteria set forth in the HIC Application Instructions 
are met, copy and paste the completed relevant section from the Instructions into this application.
7.   Investigational device accountability:
a.
State how the PI, or named designee, ensures that an investigational device is used only in 
accordance with the research protocol approved by the HIC, and maintains control of the 
investigational device as follows:
Maintains appropriate records, including receipt of shipment, inventory at the 
site, dispensation or use by each participant, and final disposition and/or the return of the 
investigational device (or other disposal if applicable):
Documents pertinent information assigned to the investigational device (e.g., date, quantity, batch 
or serial number, expiration date if applicable, and unique code number):
Stores the investigational device according to the manufacturer's recommendations with respect to 
temperature, humidity, lighting, and other environmental considerations:
Ensures that the device is stored in a secure area with limited access in accordance with applicable 
regulatory requirements:
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Distributes the investigational device to subjects enrolled in the IRB-approved protocol:
SECTION VII: RECRUITMENT/CONSENT AND ASSENT PROCEDURES 
1. Targeted Enrollment: Give the number of subjects:
a.
  targeted for enrollment at Yale for this protocol_75
b.    If this is a multi-site study, give the total number of subjects targeted across all 
sites___ 
2. Indicate recruitment methods below.  Attach copies of any recruitment materials that will be used.
 Flyers
 Internet/Web Postings
 Radio
 Posters
 Mass E-mail Solicitation
 Telephone
 Letter
 
 Departmental/Center Website
 Television
 Medical Record Review
 Departmental/Center Research Boards
 Newspaper
 Departmental/Center Newsletters
 Web-Based Clinical Trial Registries
  YCCI Recruitment database
 Clinicaltrials.gov Registry (do not send materials to HIC)
 Other (describe):
3.  Recruitment Procedures: 
a.
Describe how potential subjects will be identified.
b.
Describe how potential subjects are contacted. 
c.
Who is recruiting potential subjects? 
Any healthy person or a person with a history of pain for more than 6 weeks between the ages 
of 18-65 years old is a potential subject. Potential subjects will be identified by a call for 
subjects via flyers, business cards and ads, describing the key eligibility criteria ( 18-65 years 
old). Flyers and business cards will be posted around Yale University (see attached research 
flyers), and advertisements will be posted in local newspapers or on local websites like 
Craig’s List, the Yale University Bulletin, and websites for social networking, like the “Yalies 
in New Haven” group on Facebook (see same wording as the flyers). Interested subjects will 
contact the research coordinators at a telephone number indicated on the flyer.  During the 
initial telephone conversation, she will provide a brief description of the study, schedule the 
subject's first session, and screen the subject to ensure that they meet inclusion criteria and do 
not possess any of the exclusion criteria. We request that written informed consent and 
HIPAA authorization be waived for this part of the screening (see below).  Written informed 
consent will be obtained immediately before the first session at The John B Pierce Laboratory. 
4. Screening Procedures
a.
Will email or telephone correspondence be used to screen potential subjects for 
eligibility prior to the potential subject coming to the research office? 
 Yes  
 No
b.
 If yes, identify below all health information to be collected as part of screening and 
check off any of the following HIPAA identifiers to be collected and retained by the 
research team during this screening process. 
HEALTH INFORMATION TO BE COLLECTED:
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HIPAA identifiers: 
 Names 
 All geographic subdivisions smaller than a State, including: street address, city, county, precinct, zip codes and their 
equivalent geocodes, except for the initial three digits of a zip code if, according to the current publicly-available data from 
the Bureau of the Census: (1) the geographic unit formed by combining all zip codes with the same three initial digits 
contains more than 20,000 people, and (2) the initial three digits of a zip code for all such geographic units containing 
20,000 or fewer people is changed to 000. 
  Telephone numbers
 Fax numbers 
 E-mail addresses
 Social Security numbers 
 Medical record numbers
 Health plan beneficiary numbers 
 Account numbers 
  All elements of dates (except year) for dates related to an individual, including: birth date, admission date, discharge 
date, date of death, all ages over 89 and all elements of dates (including year) indicative of such age, except that such ages 
and elements may be aggregated into a single category of age 90 or older 
 Certificate/license numbers 
 Vehicle identifiers and serial numbers, including license plate numbers 
 Device identifiers and serial numbers 
 Web Universal Resource Locators (URLs) 
 Internet Protocol (IP) address numbers 
 Biometric identifiers, including finger and voice prints 
 Full face photographic images and any comparable images 
 Any other unique identifying numbers, characteristics, or codes 
5. Assessment of Current Health Provider Relationship for HIPAA Consideration:
Does the Investigator or any member of the research team have a direct existing clinical 
relationship with any potential subject? 
 Yes, all subjects
 Yes, some of the subjects
 No
If yes, describe the nature of this relationship.
6. Request for waiver of HIPAA authorization: (When requesting a waiver of HIPAA Authorization 
for either the entire study, or for recruitment purposes only.  Note: if you are collecting PHI as part of 
a phone or email screen, you must request a HIPAA waiver for recruitment purposes.)
Choose one: 
☐ For entire study 
For recruitment purposes only
☐ For inclusion of non-English speaking subject if short form is being used
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i. Describe why it would be impracticable to obtain the subject’s authorization for 
use/disclosure of this data;
Since we perform our screenings over the phone, it is impractical to obtain a written 
HIPAA authorization. However, once eligibility is determined and the subject is willing to 
participate, the first session will be scheduled. At the beginning of this first session we will 
obtain Compound Consent and HIPAA Research Authorization for further use of the data.
b.
i. If requesting a waiver of signed authorization, describe why it would be 
impracticable to obtain the subject’s signed authorization for use/disclosure of this 
data;
Since we perform our part of our screenings over the phone, it is impractical to obtain a 
written HIPAA authorization. Prior to obtaining consent, all participants will be screened 
on the phone by the research coordinator. During this phone conversation, the research 
coordinator will provide a brief description of the study, including information about the 
tasks the subject will have to perform, where the study is conducted, how long the entire 
study participation will take, and the amount of financial compensation. Subjects will then 
be asked to verbally consent to us asking them various questions to ensure that they meet 
inclusion criteria and do not possess any of the exclusion criteria. We will use the 
following language during our phone screening: “We will keep the information we just 
talked about in our files until you come in to the first session of the study. If you qualify 
and choose to be part of the study, this information will become part of your study file. If 
you don't come in or if you don't qualify for the study, we will keep this information until 
the study is over and then we will destroy it. We are required by law to keep this 
information confidential and we will not use it for any purpose other than to see if you 
qualify for this study and for research oversight.” If the subject is eligible and willing to 
participate, the first session will be scheduled. At the beginning of this first session we will 
obtain Compound Consent and HIPAA Research Authorization.
By signing this protocol application, the investigator assures that the protected 
health information for which a Waiver of Authorization has been requested will not 
be reused or disclosed to any person or entity other than those listed in this 
application, except as required by law, for authorized oversight of this research 
study, or as specifically approved for use in another study by an IRB.
Researchers are reminded that unauthorized disclosures of PHI to individuals outside of the Yale 
HIPAA-Covered entity must be accounted for in the “accounting for disclosures log”, by subject 
name, purpose, date, recipients, and a description of information provided.  Logs are to be 
forwarded to the Deputy HIPAA Privacy Officer.
7. Required HIPAA Authorization: If the research involves the creation, use or disclosure of 
protected health information (PHI), separate subject authorization is required under the 
HIPAA Privacy Rule. Indicate which of the following forms are being provided:
 Compound Consent and Authorization form
 HIPAA Research Authorization Form
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8. Consent Personnel: List the names of all members of the research team who will be obtaining 
consent/assent. 
Paul Geha, Dana Small, Gelsina Stanley, Roberta Delvy, Elizabeth Garcia
9. Process of Consent/Assent: Describe the setting and conditions under which consent/assent will 
be obtained, including parental permission or surrogate permission and the steps taken to ensure 
subjects’ independent decision-making. 
Prior to obtaining consent, all participants will be screened on the phone by the research 
coordinator at The John B Pierce Laboratory. During this conversation, the research coordinator 
will provide a brief description of the study, including information about tasks the subject will 
have to perform in the behavioral assessments, where the study is conducted, the medications used, 
the risks and benefits of paricipation, how long the entire study participation will take, and the 
amount of financial compensation. Subjects will also be screened to ensure that they meet 
inclusion criteria and do not possess any of the exclusion criteria. If the subject is eligible and 
willing to participate, the first session will be scheduled. Informed consent will be obtained 
immediately at the beginning of the first session. Personnel obtaining consent have a thorough 
understanding of the methodology of the protocol and a comprehensive knowledge of the 
procedures of the protocol and are capable of answering the possible questions raised by the 
potential subject regarding the study. A subject will sit down at a desk in a room. The study 
personnel will ask the subject to read through the entire compound research authorization and 
consent form. After the subject had read the entire form the researcher will verbally summarize the 
procedure, risks and steps taken to minimize risks. The subject is explicitly asked if they have any 
questions. All questions will be answered, except in the rare case that providing full disclosure 
may influence the outcome of the study (e.g. we do not want subjects to be aware that the puddings 
are manipulated in fat content). In these circumstances, the experimenter will explain that this is 
the case and offer to provide a fuller answer after the experiment. Subjects will receive additional 
details about the assessments they are to perform and will be informed that they may withdraw 
from the study at any time with no penalty. Subjects will be asked if they understand what the 
study entails and if they have had sufficient opportunity to consider whether or not to participate. If 
a subject affirms she/he will then be asked to sign the compound consent form and research 
authorization form and given a copy (attached).
10. Evaluation of Subject(s) Capacity to Provide Informed Consent/Assent: Indicate how the 
personnel obtaining consent will assess the potential subject’s ability and capacity to consent to the 
research being proposed. 
This research does not involve subjects with limited decision-making capacity. We will not recruit 
vulnerable subjects. For this reason we do not anticipate recruiting subjects without the ability and 
capacity to consent. However, we will ask subjects if they understand what the study entails and if 
they have had sufficient information and opportunity to consider whether or not to participate.
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11. Documentation of Consent/Assent: Specify the documents that will be used during the 
consent/assent process. Copies of all documents should be appended to the protocol, in the same 
format that they will be given to subjects. 
Adult compound consent and research authorization forms are attached. 
12. Non-English Speaking Subjects: Explain provisions in place to ensure comprehension for 
research involving non-English speaking subjects. If enrollment of these subjects is anticipated, 
translated copies of all consent materials must be submitted for approval prior to use. 
Our research does not involve non-English-speaking subjects.
12(a) As a limited alternative to the above requirement, will you use the short form* for 
consenting process if you unexpectedly encounter a non-English speaking individual interested 
in study participation and the translation of the long form is not possible prior to intended 
enrollment? 
YES ☐  NO ☐
Note* If more than 2 study participants are enrolled using a short form translated into the same 
language, then the full consent form should be translated into that language for use the next time 
a subject speaking that language is to be enrolled.
Several translated short form templates are found on our website at: 
 http://www.yale.edu/hrpp/forms-templates/biomedical.html. If the translation of the short form 
is not available on our website, then the translated short form needs to be submitted to the IRB 
office for approval via amendment prior to enrolling the subject. Please review the guidance and 
presentation on use of the short form available on the HRPP website.
If using a short form without a translated HIPAA Research Authorization Form, please 
request a HIPAA waiver in the section above. 
13. Consent Waiver: In certain circumstances, the HIC may grant a waiver of signed consent, or 
a full waiver of consent, depending on the study. If you will request either a waiver of consent, 
or a waiver of signed consent for this study, complete the appropriate section below.  
 
 Not Requesting a consent waiver 
 
 Requesting a waiver of signed consent
       
 Requesting a full waiver of consent
   
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A. Waiver of signed consent: (Verbal consent from subjects will be obtained. If PHI is 
collected, information in this section must match Section VII, Question 6)
 Requesting a waiver of signed consent for Recruitment/Screening only 
If requesting a waiver of signed consent, please address the following:
a. Would the signed consent form be the only record linking the subject and the research? 
 Yes  
 No
b. Does a breach of confidentiality constitute the principal risk to subjects? 
 Yes  
 No
OR
c. Does the research activity pose greater than minimal risk? 
 Yes If you answered yes, stop. A waiver cannot be granted.  Please note: 
Recruitment/screening is generally a minimal risk research activity  
 No 
AND
d. Does the research include any activities that would require signed consent in a non-
research context? 
 Yes  
 No
 Requesting a waiver of signed consent for the Entire Study (Note that an information 
sheet may be required.)
If requesting a waiver of signed consent, please address the following:
a. Would the signed consent form be the only record linking the subject and the research? 
 Yes  
 No
b. Does a breach of confidentiality constitute the principal risk to subjects? 
 Yes  
 No
OR
c. Does the research pose greater than minimal risk? 
 Yes If you answered yes, stop. A 
waiver cannot be granted.    
 No 
AND
d. Does the research include any activities that would require signed consent in a non-
research context? 
 Yes  
 No
B. Full waiver of consent: (No consent from subjects will be obtained for the activity.) 
 Requesting a waiver of consent for Recruitment/Screening only 
a. Does the research activity pose greater than minimal risk to subjects?  
 Yes  If you answered yes, stop. A waiver cannot be granted. Please note: 
Recruitment/screening is generally a minimal risk research activity 
 No
b. Will the waiver adversely affect subjects’ rights and welfare? 
 Yes  
 No
c. Why would the research be impracticable to conduct without the waiver? 
d. Where appropriate, how will pertinent information be returned to, or shared with 
subjects at a later date? 
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 Requesting a full waiver of consent for the Entire Study (Note: If PHI is 
collected, information here must match Section VII, question 6.)
If requesting a full waiver of consent, please address the following:
a. Does the research pose greater than minimal risk to subjects?  
 Yes  If you answered yes, stop. A waiver cannot be granted.  
 No
b. Will the waiver adversely affect subjects’ rights and welfare? 
 Yes  
 No
c. Why would the research be impracticable to conduct without the waiver? 
d. Where appropriate, how will pertinent information be returned to, or shared with 
subjects at a later date? 
SECTION VIII: PROTECTION OF RESEARCH SUBJECTS
    Confidentiality & Security of Data:
a.    What protected health information (medical information along with the HIPAA identifiers) 
about subjects will be collected and used for the research?   
Information about (self-reported) alcohol consumption, drug use, medical illness, 
major psychiatric illness, genetic information, brain images and use of medications 
will be collected.
c.
How will the research data be collected, recorded and stored? 
Data will consist of verbal, written, or computerized ratings of sensory stimuli, 
questionnaires, and computerized responses to the neuropsychological and 
impulsivity assessments. All data will be kept confidential. Participant information is 
maintained in computer files that are password protected, and data from individuals 
(computer files and hard copy versions) are identified only by code. Only the primary 
investigator and research staff, the Yale HIC, and the National Institute of Health, 
which sponsors the study, will have access to these files. The data will be archived in 
the same manner after the research is completed. Seven years after completion of the 
study the identifying data will be deleted by zeroing with software as in accordance 
with policies and procedures as determined by Yale University (procedures 1609 and 
1610).
c.    How will the digital data be stored? 
 CD  
 DVD  
 Flash Drive  
 Portable Hard   
       Drive  
 Secured Server  
 Laptop Computer  
 Desktop Computer  
 Other
The database with subject identifiers and means to link subject names and codes with 
research data is stored in a database in a separate location on a secured server at The John 
B Pierce Laboratory. Access to the database itself is password protected. Hardcopy PHI 
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data is in a locked cabinet. All other digital media (CD, DVD, Laptop computers) only 
contain research data that are identified by code.
d.    What methods and procedures will be used to safeguard the confidentiality and security of    
the identifiable study data and the storage media indicated above during and after the 
subject’s participation in the study?
Do all portable devices contain encryption software? 
 Yes   
 No
         If no, see http://hipaa.yale.edu/guidance/policy.html
 
 None of the portable devices contain PHI or HIPAA identifiers, and  they are password 
protected. The identifying data is stored on a password protected database on a secure 
server in The John B Pierce Laboratory. Thus identifiers are not kept on the same device 
as the study information.
d. What will be done with the data when the research is completed? Are there plans to destroy     
the identifiable data? If yes, describe how, by whom and when identifiers will be destroyed. 
If no, describe how the data and/or identifiers will be secured.
Identifying data are retained for a period of seven years after publication.
e.
Who will have access to the protected health information (such as the research sponsor, the  
investigator, the research staff, all research monitors, FDA, Yale Cancer Center Data and 
Safety Monitoring Committee (DSMC), SSC, etc.)? (please distinguish between PHI and de-
identified data) 
As NIH is funding the study, rules governing NIH access will apply. No other entities 
besides research staff and the investigator will have access to PHI or de-identified 
data, with the exception of presentations of data. These are typically reported as 
group averages. Where individual data are reported, individuals are not identified 
except by code.
g.   If appropriate, has a Certificate of Confidentiality been obtained? N/A
h.   Are any of the study procedures likely to yield information subject to mandatory reporting   
requirements? (e.g. HIV testing – reporting of communicable diseases; parent interview -
incidents of child abuse, elderly abuse, etc.). Please verify to whom such instances will need to 
be reported. N/A
SECTION IX: POTENTIAL BENEFITS
Potential Benefits: Identify any benefits that may be reasonably expected to result from the 
research, either to the subject(s) or to society at large. (Payment of subjects is not considered a 
benefit in this context of the risk benefit assessment.) 
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There are no direct benefits to participating subjects.  However, the study will help us understand 
the brain response to food in the presence and absence of opiate agonist/antagonists, which are 
highly prescribed nowadays for pain, addiction and obesity.  This understanding in turn will help 
us study the effect on body weight and behavior of prescription opiates in patients with pain.
         SECTION X: RESEARCH ALTERNATIVES AND ECONOMIC CONSIDERATIONS
1.     Alternatives: What other alternatives are available to the study subjects outside of the research?
The healthy participants for this study are not in need of treatment or seeking treatment. For this 
reason there is no alternative, except to decline participation in the study.
The pain participants might feel short-term relief of pain; If patients are interested in seeking 
such treatment they will be asked to talk to their doctor about it.
2. Payments for Participation (Economic Considerations): Describe any payments that 
will be made to subjects, the amount and schedule of payments, and the conditions for 
receiving this compensation. The subject’s payments for the open label and the randomized 
controlled study are the same per session completed. 
Remuneration is as follows for the randomized controlled study:
Type session:
payment:
frequency
Total
behavioral assessment
$ 80
x __1____
= $ __80___
fMRI scan with milkshake 
$ 100 *
x __3____
= $ __300___
Computer Games
$100
x __1____
= $ __100___
Subtotal:
= $  380_____
Completion Bonus
$ 50
x ___1___
= $ _50____
Accumulated Earnings Bonus
x ___1___
= $ Variable___
Total payment:
= $ _530_
And for the open label study:
Type session:
payment:
frequency
Total
behavioral assessment
$ 80
x 1
= $ 80
fMRI scan with milkshake 
$ 100 *
x 2
= $ 200
Computer Games 
$100
x _____
= $100_____
Subtotal:
= $ 280
Accumulated Earning Bonus
$
= $ variable___
Completion Bonus
$ 50
= $ 50
Total payment:
= $ 430
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*  If the subject spends up to 15 minutes in the scanner but do not complete the study, they will 
instead be paid $50. If the subject spends more than 15 minutes, they will receive the full $100 
regardless of study completion.
Subjects will participate in one Intake Session ($80), 3 fMRI scanning sessions (with milkshake, 
each $100), and a completion bonus of $50, leading to a maximal remuneration of $430. In 
addition to this, they make variable earnings depending on their performance on one of the 
computer tasks. 
3.
Costs for Participation (Economic Considerations): Clearly describe the subject’s costs 
associated with participation in the research, and the interventions or procedures of the study that 
will be provided at no cost to subjects.    
There are no costs to the subject.
 
4.
In Case of Injury: This section is required for any research involving more than minimal risk.
a.     Will medical treatment be available if research-related injury occurs? 
b.     Where and from whom may treatment be obtained? 
c.     Are there any limits to the treatment being provided? 
d.     Who will pay for this treatment? 
e.     How will the medical treatment be accessed by subjects? 
If the subject is injured as a result of participation in this study, treatment will be provided. The 
subject or the subject’s insurance carrier will be expected to pay the costs of this treatment. No 
additional financial compensation for injury or lost wages is available.
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