Sensory and Opioid Mechanisms of Affective Touch
Phase: EARLY_PHASE1
Conditions: Pain, Touch
Sponsor: National Center for Complementary and Integrative Health (NCCIH)

 
CNS IRB Protocol Template (12.15.15) 
 
 
  
Protocol Title: Sensory and Opioid Mechanisms of Affective Touch 
Abbreviated Title: Affective Touch 
Protocol Number: 17-AT-0075 
Date of This Submission/Version:07/27/2020, Version 1.7 
 
Principal Investigator 
M. Catherine 
Bushnell, PhD 
NCCIH 
 
Bldg 35, Rm.  
1E-450  
301-496-2222 
Mary.bushnell@nih.gov 
 
 
Human Research Protections Program Investigator and Staff Training: 
 
For this protocol, the following “Just in time” human subjects protection training courses are 
required for investigators and staff:  
 None 
 
 
Total requested accrual  
       
  30 Healthy Volunteers  
 
  
 
Project Uses Ionizing Radiation:  
 No   
 Yes   
 
IND/IDE 
 
 
 
 No   
Yes 
 
Durable Power of Attorney  
 
 No   
 Yes  
 
Multi-institutional Project 
 
 No   
 Yes  
 
 
 
 
 
Data and Safety Monitoring Board  
 No   
 Yes  
 
Technology Transfer Agreement  
 No   
 Yes  
 
Samples are being stored  
 
 No   
 Yes  
 
Flesch-Kincaid reading level of consent form: 8.3 
 
 
 

 
 
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Précis: 
 
Objective: Our recent pilot study found evidence suggesting that blocking endogenous opioid 
release increases the pleasantness associated with having the skin stroked. Deep pressure touch 
(observed in hugs and massage) also typically conveys a sense of pleasantness. This increased 
pleasantness contrasts with evidence that blocking endogenous opioid release increases pain. The 
current study will examine the role of endogenous opioids in the pleasantness of light skin 
stroking and deep pressure touch, and contrast it with their role in the unpleasantness of a painful 
heat stimulus. Further, it will examine the neural basis of observed perceptual changes, using 
fMRI.  This study constitutes the first study of the K99 phase of a K99/R00 grant application 
recently submitted to NCCIH by Dr. Laura Case. 
 
Study Population: 30 healthy participants will be enrolled in the study. 
Design: Participants will receive intravenous saline or intravenous naloxone on separate days to 
investigate the effect of mu-opioid antagonism on the intensity and pleasantness of superficial 
and deep affective touch and the intensity and unpleasantness of cutaneous heat pain.  Using a 
double-blind cross-over design, functional Magnetic Resonance Imaging (fMRI) will be 
conducted during sensory testing before and after the infusion of each drug to examine the neural 
mediation of opioid effects on touch perception. Ratings of mood, anxiety, pain intensity, 
pleasantness/unpleasantness, wanting and liking will also be collected throughout the study 
session. 
 
Outcome measures: We will compare subjective ratings (mood, calmness, anxiety, 
pleasantness, wanting, liking, pain intensity and unpleasantness) during naloxone and saline to: 
1) Determine whether naloxone increases the pleasantness and/or intensity of affective touch 
(light brush and deep compression); 2) Determine whether naloxone increases the unpleasantness 
and/or intensity of cutaneous heat pain; 3) Determine the role of mood or anxiety changes in 
mediating the effect of endogenous opioids on these perceptual measures; 3) Determine changes 
in the brain activation related to these effects. 
 
Precis posted online at clinicaltrials.gov: see Attachment 3 
 

 
 
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Table of Contents  
 
Précis: .......................................................................................................................................................... 2 
List of Abbreviations  ............................................................................................................................. 4 
1. Introduction and Background ........................................................................................................ 4 
2. Study Objectives .................................................................................................................................. 6 
3. Subjects ................................................................................................................................................... 7 
4. Study Design and Methods ............................................................................................................... 9 
5. Management of Data and Samples ............................................................................................. 16 
6. Additional Considerations ............................................................................................................ 18 
7. Risks and Discomforts .................................................................................................................... 19 
8. Subject Safety Monitoring ............................................................................................................. 22 
9. Outcome Measures .......................................................................................................................... 23 
10. Statistical Analysis ........................................................................................................................ 24 
11. Human Subjects Protection ....................................................................................................... 25 
12. Anticipated Benefit ....................................................................................................................... 27 
14. Consent Documents and Process ............................................................................................. 28 
15. Data and Safety Monitoring ....................................................................................................... 28 
16. Quality Assurance ......................................................................................................................... 29 
17. Reporting of Unanticipated Problems, Adverse Events and Protocol Deviations . 29 
18. Alternatives to Participation ..................................................................................................... 29 
19. Privacy ............................................................................................................................................... 29 
20. Confidentiality ................................................................................................................................ 29 
21. Conflict of Interest ......................................................................................................................... 30 
22. Technology Transfer .................................................................................................................... 31 
23. Research and Travel Compensation ....................................................................................... 31 
24. References........................................................................................................................................ 31 
25. Attachments/ Appendices .......................................................................................................... 35 
26. Consent Forms ................................................................................................................................ 62 
 
 

 
 
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List of Abbreviations 
 
PANAS = Positive and Negative Affect Schedule 
fMRI = Functional Magnetic Resonance Imaging 
C-LTMR = C Low Threshold Mechanoreceptors 
MRI = Magnetic Resonance Imaging 
MDMA = Methylenedioxymethamphetamine 
LSD = Lysergic acid diethylamide 
MINI = Mini-International Neuropsychiatric Interview  
NSAIDs = Nonsteroidal anti-inflammatory drugs 
CRIS = Clinical Research Information System 
CC= Clinical Center 
FMRIF = Functional MRI Facility 
NRS = Numeric ratings scale 
LIP = Licensed independent practitioner 
EPI= echo planar imaging 
BOLD= blood oxygenation level-dependent 
MP-RAGE = Magnetization Prepared Rapid Acquisition by Gradient Echo 
TCI = Temperament and Character Inventory  
BAS = Behavior Appetitive System Scale  
HADS = Hospital Anxiety and Depression Scale  
NEO (personality inventory) 
GDS = Genomic Data Sharing  
DoH = Declaration of Helsinki  
FWA= Federal wide Assurance 
CNS = Central Nervous System 
SPSS = Statistical Package for the Social Sciences 
FSL = FMRIB Software Library 
AFNI = Analysis of Functional NeuroImages 
 
 
1. Introduction and Background 
 
A better understanding of the human endogenous opioid system and its innate activation 
mechanisms is important for unraveling the neurochemical underpinnings of alternative therapies 
for depression, anxiety and pain. Here, we investigate the role of endogenous opioids in affective 
dimensions of touch and pain with the hypothesis that this system modulates the pleasantness of 
touch and the unpleasantness of pain.  
Since brain regions rich in opioid receptors, such as the insula, cingulate cortex and orbitofrontal 
[1], are activated by a subtype of unmyelinated sensory afferents (C low-threshold 
mechanoreceptor; C-LTMR) which respond particularly well to slow gentle stroking of the skin 

 
 
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and that this type of touch is perceptually pleasant ([2, 3]), it is likely that endogenous opioids 
are released by this stimulus. Primate studies have previously shown that monkeys both solicit 
and receive more grooming after opioid blockade ([4]; [5]; [6]; [7]; [8]), suggesting an increased 
wanting or liking of social touch under reduced opioid levels. Similarly, in humans, we have 
some preliminary evidence that pleasantness ratings of gentle skin stroking increase after opioid 
blockade by naloxone [9], suggesting that reduced opioid levels actually make touch more 
pleasant and desirable. However, it is not clear whether the perceptual effect of blocking 
endogenous opioids is due to a direct effect of opioids on the sensory pathways or is an indirect 
effect caused by the opioids modulating mood and mood in turn modulating touch perception 
[10]. The possibility of the indirect effect is supported by data showing that opioid blockade 
leads to a negative mood state [11]; [12]; [13].  One theoretical hypothesis is that a negative 
mood state increases the hedonic value of social touch [10].  
 
A parallel system to the skin’s C-LTMRs may be present in form of unmyelinated pressure-
sensitive afferents identified in skeletal muscle and tendon of cat [14] which may mediate the 
pleasurable experience of deep pressure touch. In humans, deep pressure touch has been shown 
to reduce anxiety [15], pain and unpleasant affect [16]. For the beneficial effects of massage 
therapy [17], the exertion of moderate pressure (compared to light pressure or vibration) is 
necessary and leads to greater reduction of stress and anxiety as well as higher pleasantness 
ratings [18]. Both light skin stroking and deep pressure touch are components of numerous 
complementary health techniques which significantly reduce depression, stress, and pain [19, 
20]. By including deep pressure touch as a condition in our current study we aim to investigate, 
through blockage of the endogenous opioid system (naloxone administration), if the pleasantness 
of light skin stroking and the pleasantness of deep pressure touch are both similarly dependent on 
endogenous opioids, and whether mood mediates this effect.   
 
Endogenous opioids are central to the perception of pleasure and reward (wanting and liking) 
which serve as crucial balancing systems for pain and associated psychiatric conditions. To 
address the question of pain modulatory properties of the endogenous opioid system, specifically 
on the affective component of pain, we include an experimental heat pain condition in our study 
and administer an opioid blockade (naloxone). Previous studies of the effect of blocking opioid 

 
 
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receptors on pain perception have produced conflicting results: no effect on pain [21-24], 
increased pain following high dose and decreased pain at low dose naloxone[25-28]. The same 
contradictory findings are true for several rodent studies [29-32]. To our knowledge, the ratings 
in the human studies were all unitary measures of pain intensity. However, a more recent study 
on this topic [33] utilized rating systems for both pain unpleasantness and pain intensity allowing 
the authors to differentiate the affective component of pain. The opioid blockade significantly 
increased pain unpleasantness ratings of experimental pain but the pain intensity ratings 
remained unaffected [33]. Our aim is to replicate this finding and add to it brain imaging data 
(fMRI) to characterize the brain areas associated with producing this dichotomized pain 
perception. By deciphering this neuronal process we could potentially also understand how mood 
can alter pain unpleasantness independent of pain intensity [34], if understood these components 
strengthen therapeutic strategies for treatment of chronic pain using mood altering therapies. 
2. Study Objectives  
 
Hypothesis 1 (primary outcome): Participants will experience a significant increase in the 
pleasantness but not intensity of cutaneous brushing and deep skin/muscle pressure after 
administration of naloxone (compared to saline). 
 
Hypothesis 2 (secondary outcome): Participants will experience a significant increase in the 
unpleasantness but not intensity of cutaneous heat pain after naloxone administration. 
 
 Hypothesis 3 (secondary outcome): The effect of endogenous opioids on perception will be 
partially mediated by changes in mood, with negative mood increasing the pleasantness of 
pleasant touch and increasing the unpleasantness of pain. 
 
Hypothesis 4 (secondary outcome): Stimulus-evoked neural activations will be modulated by 
naloxone administration, with preferential effects in cingulate cortex and insula.  
 

 
 
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3. Subjects 
 
a.  Description of study populations 
 
Based on our power calculations, we would like to have 24 healthy men and women who meet 
the inclusion/exclusion criteria described below participate in the study.  Because of possible 
dropouts during the study, we will set our maximum accrual at 30 participants (see detailed 
explanation of sample size estimate on p. 23).  Withdrawals/dropouts will be replaced. In 
accordance with HRPP SOP 14F and provided they are not subordinates, relatives, or co-workers 
of the investigators, or NCCIH DIR employees, NIH employees may participate in this study. 
 
b.  Inclusion criteria 
 
All subjects must be: 
1. Between 18 and 50 years old. 
2. Right-handed (on Edinburgh Handedness Inventory [53]). 
3. Fluent in English. 
4. Able to provide written informed consent. 
 
c.  Exclusion criteria 
 
Overall exclusion criteria for the study 
 
1. 
Unable to comply with study procedures (or does not rate stimuli as tolerable) or unable 
to schedule visits promptly (including inability to schedule the second session within 
approximately 14 days of the first session) 
2. 
Pregnancy or breastfeeding. 
3. 
Use of recreational drugs in the past month (e.g., marijuana, MDMA [“ecstasy” or 
“molly”], LSD, cocaine, methamphetamine, heroin, prescription and/or opioids). 
4. 
Congenital lower limb deficiency or amputation. 
5. 
Peripheral neuropathy, dermatological condition such as scars or burns, or has had a 
tattoo in the testing region within the previous four weeks that might influence 
cutaneous sensibility. 

 
 
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6. 
Women who consume more than 7 alcoholic beverages per week, and men who 
consume more than 14 drinks per week.  
7. 
Current chronic pain condition or has had chronic pain in the past year (painful 
condition lasting more than six months), including ongoing treatment with medications 
for neuropathic pain (e.g. gabapentin, tricyclic antidepressants, pregabalin, tramadol) 
8. 
Major medical condition, such as kidney, liver, cardiovascular (including blood clots, 
hypertension, preexisting cardiac arrhythmia), autonomic, pulmonary, or neurological 
problems (e.g., seizure disorder ) or a chronic systemic disease (e.g., diabetes). 
9. 
Current diagnosis or pharmacological treatment of psychiatric disorders such as major 
depression, major anxiety-related problems, post-traumatic stress syndrome, bipolar 
disorder, psychosis, attention-deficit/hyperactivity disorder or current or lifetime 
alcohol or substance abuse disorders (as identified in study #16-AT-0077) 
10. 
Participant has metal in his/her body which would make having an MRI scan unsafe, 
such as pacemakers, medication pumps, aneurysm clips, metallic prostheses (including 
metal pins and rods, heart valves or cochlear implants), shrapnel fragments, permanent 
eye liner or small metal fragments in the eye that welders and other metal workers may 
have. 
11. 
Participant is uncomfortable in small closed spaces (has claustrophobia) so that he/she 
would feel uncomfortable in the MRI machine or cannot lie comfortably flat on his/her 
back for up to 75 minutes in the MRI scanner.  
12. 
Participants weighs more than 550 lbs.  
13. 
Participant has taken any pain medication other than an over-the-counter NSAIDs or 
acetaminophen within the last month or for more than one month on a continual basis 
within last six months. 
14. 
Previous participation in 13-AT-0143 (related study). 
15. 
NIH employees who are subordinates, relatives, or co-workers of the investigators, or 
NCCIH DIR employees. 
16. 
Participants using medications that play into opioid pathways (e.g. loperamide or 
dextromethorphan), that could potentially interact with naloxone (naltrexone, 
methylnaltrexone, droperidol, fenfluramine and clonidine)  

 
 
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17. 
Participant using any herbal supplements (such as yohimbine) due to risk of unknown 
dangerous interaction as there is no data for herbal preparations and naloxone. 
18. 
Participant has allergies to naloxone or similar drugs. 
 
Exclusion criteria for individual study session 
1. 
Has consumed alcohol within 24 hours, shows signs of alcohol withdrawal syndrome, 
or has behavioral signs of intoxication will be excluded immediately and not have the 
possibility to reschedule their session. 
2. 
Used topical pain-relieving creams in the testing area (e.g. methylsalicylate, capsaicin) 
within 24 hours of testing or used non-steroidal anti-inflammatory drugs (NSAIDS, e.g. 
aspirin, ibuprofen), acetaminophen, or naproxen within 3 days of testing. * 
* To be determined during the pre-session screening (see Attachment 2: Pre-Session Screening). 
Participants who cannot refrain from these activities may have their session rescheduled up to 
two times. If the participant is found non-compliant during the second rescheduled appointment, 
he or she will be excluded from the study. 
 
An Eligibility Checklist can be found in Attachment 2. 
4. Study Design and Methods 
 
a. 
Study overview  
 
Healthy male and female volunteers will be recruited and informed that they may be eligible to 
participate in a study that examines the role of endogenous opioids in processing several types of 
touch. We will explain that participants will receive saline and naloxone on two different days 
with a minimum 24 hour wash-out period between testing sessions to minimize the possibility of 
carry-over effects, serum half-life for naloxone ranges from 30 to 81 minutes. The drugs will be 
administered in association with different types of touch stimuli on the calf of the leg including 
light brush stroking of the skin, compression around the limb, and application of heat to the skin, 
including moderately painful heat.  Functional magnetic resonance imaging (fMRI) will be 
conducted simultaneously to observe the effect of the drug infusions on touch processing.  The 

 
 
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purpose of the study is to identify the role of endogenous opioids in perception of light and deep 
pressure touch as well as experimental pain. 
 
A pre-screening telephone call will be conducted to determine eligibility. If eligibility 
requirements are met, subjects will be scheduled for the test sessions.  Screening will be 
accomplished under NCCIH protocol 16-AT-0077 (“Clinical and Scientific Assessment of Pain 
and Painful Disorders”). If deemed eligible, the participant will provide consent for the current 
protocol prior to performing any procedures specific to this protocol. Consent may occur during 
an additional, separate visit from the subsequent two research sessions.  See Figure 1 for Study 
Flow. All visits will be on an outpatient basis and all experiments will be conducted in Building 
10 of the NIH.  
 
All subjects will be informed about naloxone, including its pharmacological properties, clinical 
use, and possible side effects.  Subjects will also be informed that they may withdraw from 
participation at any time during the course of the study and that they will be compensated for each 
portion of the study that they have completed. 
Figure 1.  Study Flow.  Each MRI session will follow the timeline shown. 
 
 
 
 
 

 
 
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b. Recruitment 
 
We anticipate recruiting up to 30 potential participants.  Participants may be recruited from a 
currently active NCCIH Phenotyping protocol (16-AT-0077).  Participants may also be recruited 
from the NIH Clinical Trial recruiting line (1-800-411-1222).  When a potential subject contacts 
us, he or she will be scheduled for a telephone pre-screening session (described below).  Cold-
calling will not be used to contact or recruit potential participants.  NIH employees will not be 
directly recruited by or through their supervisors to participate in this study. NCCIH employees 
cannot participate in this protocol. 
 
Telephone Interview (pre-screening) 
Each potential participant will undergo a telephone pre-screening interview of approximately 15 
minutes (see Attachment 1 for details).  During the telephone interview, the subject will be 
informed about the general procedures of the study, and inclusion/exclusion criteria will be 
assessed.  If the potential subject does not meet these criteria, the interview will be terminated and 
screening information will be destroyed.  However, if the potential participant agrees, we will 
retain their contact information to contact them later about other studies in the lab for which they 
may be eligible (including name, email, and phone number).  Potentially eligible subjects will be 
told that to serve as participants they will be required to undergo a drug screening and, for 
participants who can become pregnant, a pregnancy test. If the potential subject agrees to continue 
to participate, they will be scheduled for their first session.  Further screening information will be 
drawn from previous participation in the NCCIH Phenotyping Protocol, 16-AT-0077.  Participants 
will be informed of this. 
c. 
Screening 
 
Screening 
 Screening for this protocol is done under NCCIH protocol 16-AT-0077 (“Clinical and Scientific 
Assessment of Pain and Painful Disorders”).  Screening will be done within a year of participation 
in this protocol and data required includes clinical MRI, medical exam, psychological interview, 
sensory testing and the Edinburgh Handedness Inventory. If deemed eligible, the participant will 

 
 
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provide consent for the current protocol prior to performing any procedures specific to this 
protocol.   
Once enrolled in T-AT-0285, a LHP will review eligibility criteria at the beginning of each 
session, and confirm that participants are eligible and meet pre-session criteria.  
 
d. Study procedures 
 
Consent will be obtained before any study procedures will be done.  Upon arrival at the Clinical 
Center, the participant will be assigned a CRIS identification number through the NIH 
Admissions Office.  The consent form will be explained and all questions will be answered 
before the participant is asked to sign the consent form (see Section 14 for details).  Consent may 
occur during an additional, separate visit from the subsequent two research sessions. 
 
Participants eligible to proceed will be asked to undergo two testing sessions, separated by at 
least 1 day, in the NIH Clinical Research Center’s Functional MRI Facility (FMRIF, Building 
10, Room B1D307 or B1D305).  Each participant will receive naloxone on one day, and saline 
on the other, with drug order counterbalanced across subjects.  At each visit, a urine sample will 
be collected from all participants for drug screening. In addition, at each visit, participants who 
are able to become pregnant will also take a urine pregnancy test. Date of onset for previous 
menstrual cycle will be documented to allow for later analysis of confounds of menstrual cycle 
in perceptual outcomes. Medical inclusion and exclusion criteria will be reviewed with the 
participant at the beginning of each study session to confirm continued eligibility.  The 
participants will have their intravenous line placed before any part of the fMRI will start. A 
baseline scan including data collection for all sensory conditions will be collected before the 
intravenous infusion. Drug infusion will then start with a bolus injection followed by a 
continuous infusion of naloxone or saline and the full sensory paradigm will be repeated. An 
anatomical MRI will also be acquired. 
 
Sensory testing paradigm 
Sensory testing will occur on the participant’s left lower leg.  While it is most common for 
brushing paradigms to brush on the hairy skin on the arm (C-LTMR fibers primarily innervate 

 
 
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hairy skin), several studies have reported the same preference for slow, C-LTMR brushing on the 
leg [35], including the shin [36].  According to our unpublished data the calf is also a site of high 
pleasantness ratings for deep compression, and more accessible in the MRI scanner.  We will 
therefore conduct all sensory testing on subjects’ lower leg.  Participants will be asked to wear 
shorts or change into scrubs for each session in order to access the lower leg. 
During each period of fMRI recording (before and after drug infusion) we will administer six 
stimulus blocks (approx.5 min each). Each block will contain only one type of stimulus (fast or 
slow brushing, high or low pressure, high or low heat), with stimuli lasting 10-30 sec and inter-
stimulus-intervals of at least 15 sec. Gentle brushing will be performed at two speeds (~3cm/s 
and ~30 cm/s) using a soft brush.  A trained experimenter blind to the drug condition will 
administer the brushing, using audio or visual cues to keep the correct rate of brushing.  Since 
the subject will be in the MRI scanner throughout all stimulation, the experimenter will not be 
visible to the subjects, thus eliminating interpersonal cues. Deep pressure will be administered 
using an inflatable compression cuff designed by the NIH Clinical Center machine shop.  Similar 
to a blood pressure cuff, the inflatable cuff will wrap around the participant’s lower leg and will 
inflate to a pleasant pressure and a less pleasant pressure (both less than 120 mmHg). Heat 
stimuli will be administered by the trained experimenter using a contact thermode (Medoc 
Pathway System; Medoc Ltd., Advanced Medical System, Israel). Heat will be approximately 
46οC (painful) and approximately 41οC (non-painful).  Similar painful heat stimuli have been 
used in our lab and elsewhere, including in approved NIH protocols [37].   
 
After each stimulus block, subjects will provide ratings of pain intensity, 
unpleasantness/pleasantness, bad mood/ good mood, anxiety/calm, wanting and liking (see 
below and Attachment 2). We will use stimulus presentation software such as e-prime or matlab 
for stimulus presentation and recording of ratings.  NRS ratings of current ongoing pain and 
discomfort will be taken after functional MRI scans.  
 
Drug Administration 
All study participants will receive both drug conditions (naloxone and saline), one at each 
experimental session.  Both substances will be administered intravenously by licensed providers. 
For naloxone, to achieve a constant plasma level throughout the ~45 min testing phase, a bolus 

 
 
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dose of naloxone (0.05 mg/kg bodyweight; generic) will administered as a manual injection, via 
an intravenous line, followed by a pump administered intravenous infusion of 0.08 mg/kg/h 
starting immediately after the bolus injection and continuing for the duration of the scan.  A 
maximum dose of 10mg naloxone will be administered, which is the maximum dose used 
clinically to reverse the effects of opiates (Micromedex).  Individuals over 200lb will receive a 
slightly lower dose per body weight in order to not exceed the 10mg maximum.  We have 
previously used this dosage and administration procedure for healthy subjects and fibromyalgia 
patients in Protocol 13-AT-0143.   The saline will be administered in the same fashion, i.e. as a 
manual bolus injection followed by a pump administered infusion of saline, both using the same 
volume per individual as calculated for the naloxone bolus and infusion (based on body weight).  
All solutions will be prepared by the Clinical Center pharmacy and furnished to the investigators 
in individual subject doses on the day of the experiment for that subject.  Respiration rate, blood 
oxygen saturation, heart rate and blood pressure will be monitored by a nurse or nurse LP during 
both infusions.  The participants are under continuous visual monitoring when in the MRI-
scanner via a camera. Participants will be equipped with a panic button to press in case of any 
subjective need to be immediately evacuated from the MRI scanner. A crash cart is available on 
site at all times and the MRI-scanner facilities are code team accessible. The procedure described 
above has been successfully used in healthy volunteers and fibromyalgia patients under similar 
circumstances, with no significant adverse effects (eg [38] [9]; NIH protocol 13-AT-1043). At 
the end of each session, subjects will be asked to rate naloxone-related adverse effects (dry 
mouth, dry skin, blurred vision, sedation, nausea, dizziness, headache) on a scale from 0=non-
existent to 6=extremely strong. The administration of naloxone will be performed by a nurse 
practitioner or registered nurse in the Functional MRI Facility (FMRIF), and neither the 
experimenter nor the subjects will know which substance was administered on which day until 
after the study is complete.  Participants will be observed for 60 minutes after the infusion has 
been discontinued (approx. one half-life of naloxone) to ensure that participants are not 
experiencing any adverse effects. 
MRI Data Acquisition 
Functional scan: Each participant will be scanned on a 3T MRI scanner using a standard head 
coil.  During each session, two fMRI scans (containing multiple runs) will be collected using a 
blood oxygenation level-dependent (BOLD) protocol with a T2*-weighted gradient echo planar 

 
 
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imaging (EPI) sequence.  During the functional scans heart rate, blood oxygenation, and 
respiration rate will be monitored.  We will use a 3D MP-RAGE (Magnetization Prepared Rapid 
Acquisition by Gradient Echo) T1-weighted sequence for the anatomical scan.  Including the 
functional and anatomical scan, subjects will be continuously in the scanner for approximately 
75 min (see Figure1). 
 
Visual Analogue Scales 
Separate scales (see Attachment 3) will be used to assess sensory intensity/pain, 
unpleasantness/pleasantness, mood, and anxiety at baseline and throughout each session using a 
computer presentation method.  Participants will use a mouse to log their ratings.  Pain intensity 
will be assessed on a scale ranging from no sensation (-100) to pain threshold (0), to intolerable 
pain (100). Sensory hedonics (unpleasantness vs. pleasantness) will be assessed on a scale 
ranging from extremely unpleasant (-100) to neutral (0), to extremely pleasant (100).  Mood will 
be assessed on a scale ranging from extremely bad mood (-100) to neutral mood (0), to 
extremely good mood (100), anxiety will be assessed on a scale ranging from extreme anxiety (-
100) to neutral (0) to extreme calm (100), wanting will be assessed on a scale ranging from not at 
all (-100), to neutral (0),  to very much (100) and liking will be assessed on a scale ranging from 
not at all (-100), to neutral (0), to very much (100).  These scales have been used previously to 
separate the intensity and hedonic components of pain perception (eg.[39] [40]). 
 
Questionnaires 
Participants will fill out several questionnaires before or after the first test session: the 
Temperament and Character Inventory (TCI), which includes dopamine-related traits [41], the 
Behavior Appetitive System Scale (BAS) [42], the Hospital Anxiety and Depression Scale 
(HADS) to evaluate anxiety [43], the NEO Personality Inventory [44], and the Social Touch 
Scale [45].  If there is not sufficient time to complete all questionnaires during the first session, 
those questionnaires will be completed during another session of the study.  At the end of each 
session participants will be asked whether they believe they received saline or naloxone that day. 
 
e. 
End of participation 
 

 
 
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Participation will be complete upon completion of the procedures described above. Because 
participants are healthy volunteers, the only information to be shared would be incidental 
findings from their medical exam. 
5. Management of Data and Samples 
 
a. 
Storage 
 
After every scanning and behavioral session, all data collected will be de-identified and coded. 
This includes behavioral measures (e.g., pain reports, reaction time), structural and functional 
MRI data.  Data recorded manually on paper will be entered into computer files.  All de-
identified data will be stored on password protected NCCIH computers and on secure lab servers 
hosted by NINDS.  All paper questionnaires and forms completed by the subjects will be 
securely kept in locked drawers in the laboratory/office space of the Principal Investigator.  The 
lab is locked when not occupied. Only study investigators will have access to the data.  
 
b. Data (including genomic data) and sample sharing plan 
 
As no large scale genomic data will be acquired during the course of this protocol, this protocol 
is not subject to the NIH Genomic Data Sharing (GDS) policy.  
 
Data will be shared with Qualified investigators at NIH or other institutions, including our 
collaborator on this study, Hakan Olausson (Linkoping University, Sweden) 
 
Data may also be shared with collaborating laboratories at NIH or outside of NIH and/or 
submitted to NIH-designated repositories and databases if consent for sharing was obtained.  
Repositories receiving data from this protocol may be open-access or restricted access.  
 
Data will be stripped of identifiers and may be coded (“de-identified”) or unlinked from an 
identifying code (“anonymized”). When coded data is shared, the key to the code will not be 
provided to collaborators, but will remain at NIH.  Data and samples may be shared with 
investigators and institutions with an FWA or operating under the Declaration of Helsinki (DoH) 
and reported at the time of continuing review.  Sharing with investigators without an FWA or not 

 
 
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operating under the DoH will be submitted for prospective IRB approval.  Submissions to NIH-
sponsored or supported databases and repositories will be reported at the time of Continuing 
Review.  Submission to non-NIH sponsored or supported databases and repositories will be 
submitted for prospective IRB approval. 
 
Required approvals from the collaborating institution will be obtained and materials will be 
shipped in accordance with NIH and federal regulations.    
 
NCCIH specific information on data sharing: 
Samples and data may be shared with: 
1. Qualified investigators at NIH: For this purpose, investigators will first agree to a 
data use policy and data will be transferred via methods that limit the chance of 
others gaining access, such as using a secure file transfer protocol (sftp) or 
restricted access file hosting sites such as nihcesaev.cit.nih.gov.  
2. Data will be transferred using secure file transfer protocols. Investigators will be 
allowed to download data after they agree to a data use policy.  Some data 
repositories have their own data use agreement, while others allow the submitter 
to provide his/her own data use policy.  Examples of such repositories include the 
NITRC (Neuroimaging Informatics Tools and Resources Clearinghouse, 
www.nitrc.org), the XNAT Central (eXtensible Neuroimaging Archive Toolkit, 
central.xnat.org), OpenfMRI (OpenfMRI.org), PAIN (Pain and interoceptive 
imaging network, www.painrepository.org), INCF Dataspace (International 
Neuroinformatics Coordinating Facility, www.incf.org), 1000 Functional 
Connectomes and NIDAG (Neuroimaging Data Access Group, www.nidag.org). 
New data repositories are being created periodically with the intent to facilitate 
collaboration between research groups with distinct areas of expertise and thus, 
data collected under this protocol may be contributed to other data repositories not 
explicitly listed here. Data will only be placed in repositories where access to the 
data can be restricted to people who accept the data use guidelines and have an 
account and password that are linked to a valid email address. 

 
 
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o   In addition to anatomical and functional MRI images, demographic data such 
as age and handedness, neuropsychological data such as personality measures 
and IQ, and behavioral data such as performance on a task, may also be shared.  
As this protocol concerns studies of brain function in healthy volunteers, no 
participant has a diagnosed mental health disorder, and there is no risk that 
such information might be disclosed.  Thus, the risk to a participant from 
sharing their de-identified data is minimal.  Depending on the situation, a 
Global Unique Identifier (GUID) code may be attached to an individual’s data 
prior to sharing or uploading to a repository.  When GUID codes are used, only 
researchers who already have access to someone’s personal information can 
access the code.  
6. Additional Considerations 
 
We will be using naloxone at normal clinical doses as the study drug. Naloxone is an opiate 
antagonist and has been used since the 1960’s to reverse the effects of opiate overdoses.  The 
five conditions specified by the FDA for an Exemption for Clinical Investigations involving a 
Lawfully Marketed Drug (21CFR312.2(B)) are:  
“(i) The investigation is not intended to be reported to FDA as a well-controlled study in 
support of a new indication for use nor intended to be used to support any other significant 
change in the labeling for the drug; 
(ii) If the drug that is undergoing investigation is lawfully marketed as a prescription drug 
product, the investigation is not intended to support a significant change in the advertising for 
the product; 
(iii) The investigation does not involve a route of administration or dosage level or use in a 
patient population or other factor that significantly increases the risks (or decreases the 
acceptability of the risks) associated with the use of the drug product; 
(iv) The investigation is conducted in compliance with the requirements for review set forth 
by an IRB (21CFR56) and the requirements for informed consent (21CFR 50); and  
(v) The investigation is conducted in compliance with the requirements of 21CFR 312.7 
(Promotion and sale of investigational drugs).” 

 
 
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We believe our use of naloxone meets all five of these conditions.  (1) Our investigation is not 
intended to support a new indication for use of naloxone nor is it intended to support any change 
in the labeling of the drug. (2) Our investigation is not intended to support a change in the 
advertising for naloxone. (3) The intravenous route of administration for naloxone in this study is 
currently an approved route of administration and the dosage we will use is within the normal 
clinically used range. (4) Our investigation will be conducted in compliance with the 
requirements of the NIH Neuroscience IRB. (5) The investigation is conducted in compliance 
with the promotion and sale of investigational drugs. 
 
a. 
Research with investigational drugs or devices 
 
N/A 
 
b. Gene therapy 
 
N/A 
7. Risks and Discomforts 
 
The nature of the study requires the application of hot painful stimuli. However, these stimuli 
have been used in previous studies, have proven to be easily tolerated, and do not cause 
permanent tissue damage.  A risk of the screening procedures is the results of the drug tests, 
which will remain documented in the participant’s medical record. However, the participants will 
be informed of this during the telephone pre-screening procedure and asked if they want to 
continue.  If they choose to continue, they will be reminded again during the consenting process. 
 
Risks for MRI and fMRI: 
People are at risk for injury from the MRI magnet if they have pacemakers or other implanted 
electrical devices, brain stimulators, some types of dental implants, aneurysm clips (metal clips 
on the wall of a large artery), metallic prostheses (including metal pins and rods, heart valves, 
and cochlear implants), permanent eyeliner, implanted delivery pump, or shrapnel fragments. 
Welders and metal workers are also at risk for injury because of possible small metal fragments 
in the eye of which they may be unaware. Subjects will be screened for these conditions before 

 
 
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having any scan, and if they have any, they will not receive an MRI scan. In addition, all 
magnetic objects (for example, watches, coins, jewelry, and credit cards) must be removed 
before entering the MRI scan room. 
 
It is not known if MRI is completely safe for a developing fetus. Therefore, all women of 
childbearing potential will have a pregnancy test performed no more than 24 hours before each 
MRI scan. The scan will not be done if the pregnancy test is positive.  
 
People with fear of confined spaces may become anxious during an MRI. Those with back 
problems may have back pain or discomfort from lying in the scanner.  The noise from the 
scanner is loud enough to damage hearing, especially in people who already have hearing loss. 
Subjects will be fitted with hearing protection. Subjects will be instructed to let us know right 
away should the hearing protection come loose during the scan. Subjects will also be instructed 
to notify the investigators if they have hearing or ear problems. Subjects will be asked to 
complete an MRI screening before having the MRI. There are no known long-term risks of MRI 
scans. 
 
Risks and discomforts associated with an intravenous line:  
The risks of an intravenous catheter include bleeding, infection, or inflammation of the skin and 
vein, with pain and swelling. 
 
Risks and discomforts associated with naloxone: 
Naloxone is an opiate antagonist and is clinically available and commonly used to reverse the 
adverse effects of opiates, such as remifentanil. Naloxone does not produce respiratory 
depression, psychotomimetic effects or pupillary constriction.  Naloxone has not been shown to 
produce tolerance or cause physical or psychological dependence.  In the presence of opioid 
dependence, naloxone may produce withdrawal symptoms.  While the mechanisms of action of 
naloxone is not fully understood, most evidence suggests that naloxone antagonizes the opioid 
effects by competing for the μ, κ, and σ opiate receptor sites in the CNS, with the greatest 
affinity for the μ receptor.  Following parenteral (outside the intestine) administration, naloxone 
is rapidly distributed in the body and readily crosses the placenta.  Plasma protein binding occurs 

 
 
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but is relatively weak.  Plasma albumin is the major binding constituent but significant binding 
of naloxone also occurs to plasma constituents other than albumin. Naloxone is metabolized in 
the liver, primarily by glucuronide conjugation with naloxone-3-glucoronide as the major 
metabolite.  The serum half-life ranges from 30 to 81 minutes (mean 64 ± 12 minutes). 
 
Naloxone is generally thought to be well tolerated and safe. Most of the potential risks associated 
with naloxone are specific to its precipitating opiate withdrawal and do not apply to its use when 
patients have no opiates in their system, such as is the case with our study. The most common 
side effects that have been reported when naloxone is given post-operatively are nausea and 
vomiting, reversal of pain relief, agitation, and increased or decreased blood pressure. Adverse 
cardiovascular effects have occurred most frequently in postoperative patients with preexisting 
cardiovascular disease or in those receiving other drugs that produce similar adverse 
cardiovascular effects.  In experimental studies in subjects not taking opiates (as in our study), 
the only reported side effects are dry mouth and dizziness.  It is important to note that 
experimental and clinical studies with naloxone have been successfully conducted since the 
1960’s. 
 
Risks and discomforts associated with heat pain stimuli 
Several different sites are stimulated in order to minimize sensitization of the skin. However, 
reddening of the skin might occur. This is transient and disappears after termination of the 
testing. The heat stimuli, which are of moderate to strong intensity, will not damage the skin. 
Heat pain stimulation has been used extensively without any long-term adverse effects [37, 40, 
46]. 
 
Risks and discomforts associated with brushing and compression stimuli 
There are no known risks of the gentle brushing.  Pressure stimuli may be uncomfortable to 
some participants, but the pressure will be lower than a standard blood pressure cuff and thus 
familiar to all participants.  Repeated inflation could dislodge any active blood clots in the 
participant’s leg, so all participants will be checked during medical screening to ensure they do 
not have any clinical signs of clots present. 
 

 
 
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Risks and discomfort associated with physiological monitoring 
There is no medical risk associated with physiological monitoring.  The belts used for respiration 
monitoring can feel uncomfortable to certain individuals when first attached but this usually 
subsides. 
 
Risks for screening and questionnaires 
We have included a number of validated questionnaires to assess variations across individuals. 
Some of these items include sensitive questions about one’s psychological and emotional state.  
Participants will be informed that they can skip any questions they do not wish to answer, and 
that participation is voluntary.   
8. Subject Safety Monitoring 
 
Participants will be monitored by the study investigators during all study visits for study 
outcomes and adverse events. All subjects will be instructed about, and receive practice with, 
each test before they begin to perform it and, before a test is formally administered, adequate 
comprehension of the instructions for each test will be insured by the test examiner.  
 
During an assessment, testers are usually in the room with the subject or in the room just outside 
the fMRI room.  Study staff will monitor individuals during participation and subjects will be 
encouraged to tell experimenters of any discomfort.  If apparatus, etc., cannot be adjusted to 
relieve discomfort, the experiment will be stopped.  Subjects may withdraw at any time. 
 
During MRI scanning, subjects will be given a call button and instructed to use it in case of 
emergency or if the subject feels any discomfort in the scanner. Throughout the scan session, 
verbal contact with the subject will be maintained from the control room via an intercom device. 
Participants can withdraw from this study at any time and for any reason without loss of 
benefits or privileges to which they are otherwise entitled or prohibition from enrolling in other 
clinical protocols. Investigators can remove a participant from the study if an exclusionary 
condition develops, if the investigator believes that continuation is not in the best medical 
interest of the subject, or if the subject is unable to comply with study requirements. Sessions 

 
 
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may also be terminated early due to factors that do not directly influence subject safety, such as 
technical difficulties (e.g. equipment malfunction, computer issues), if schedule conflicts arise 
(e.g. participant arrives late or needs to leave early; MRI scanner availability is not sufficient to 
complete the experiment; delays in Clinical Center waiting time, time to process lab orders and 
lab results).  When sessions are terminated early, participants may be asked whether they wish 
to reschedule. If participants end a session due to discomfort, they will be asked whether they 
want to continue with other phases of the study, and/or participate in other sub-studies in the 
protocol. 
A. Withdrawal Criteria 
Participants can withdraw from this study at any time and for any reason without loss of benefits 
or privileges to which they are otherwise entitled, or prohibition from enrolling in other clinical 
protocols. Investigators can remove a participant from the study if an exclusionary condition 
develops, if the investigator believes that continuation is not in the best medical interest of the 
subject, or if the subject unable to comply with study requirements.  
B. Criteria for Stopping study 
In all subjects, procedures will be stopped if requested by participants or if the 
investigators feel it is in the best interest of the participant. 
9. Outcome Measures 
 
a. 
Primary outcome measures 
 
The primary outcome is the change or difference in pleasantness rating between post-drug and 
pre-drug of light stroking. 
 
b. Secondary outcome measures 
 
The secondary outcomes include change or differences between post-drug and pre-drug ratings 
for 1) pleasantness and/or intensity of deep pressure 2) unpleasantness and/or intensity of 
cutaneous heat pain.)  
 
c. Tertiary outcome measures 

 
 
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1) Determine the role of mood or anxiety changes in mediating the effect of endogenous opioids 
on these perceptual measures; 2) Determine changes in the brain activation related to these 
effects. 
10. Statistical Analysis 
 
a. 
Analysis of data/ study outcomes 
 
Testing for normal distribution 
All data will be assessed for normality of distribution using the Shapiro Wilk W test. A 
significant W statistic indicates that the hypothesis of a normal distribution should be rejected, 
i.e. a significant W indicates skewed data. If the data is skewed the data transformation method 
will be chosen based on the distribution (Box-Cox method) of the dependent variable. The 
resulting transformed data will be analyzed with parametric statistics. In the descriptions below 
we will describe the parametric statistical tests. If data transformation does not work, non-
parametric tests will be applied. 
 
Behavioral Data 
All behavioral data will be analyzed using SPSS or similar statistical package.  A significance 
level of p<0.05 will be adopted for all analyses.  
 
For the primary and secondary outcomes, we will use paired t-test to evaluate the drug effect. To 
determine whether the effect of drug on touch pleasantness is mediated by mood, we will use 
Wager & Lindquist’s Multilevel Mediation and Moderation (M3) Toolbox. In the analysis, the 
dependent variables are the sensory ratings, the independent variable is the drug and the mediator 
variable is mood.  
 
MRI data will be analyzed using standard brain imaging packages such as FSL or AFNI. For the 
initial analysis, the individual performing the analysis will be blinded. Whole brain analysis will 
be the first analysis performed followed by analysis looking at individual activations (parameter 

 
 
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estimates) in regions of interest including the insula, cingulate cortex and orbitofrontal cortex. 
These activations will be used to conduct a mediation analysis of these brain areas in mediating 
the effect of drug on touch pleasantness ratings. In this analysis, the dependent variables are the 
perceptual ratings, the independent variable is the level of stimulus and the mediator is the 
BOLD activation in the brain area of interest (ROI).  
 
b. Power analysis  
 
In order to yield meaningful statistical analyses of the psychophysical data, and specifically for 
our primary outcome measure, we estimate that the sample size required to complete the study 
would be 24 healthy participants. G*Power (http://www.gpower.hhu.de) was used to compute 
the necessary sample size.  We used a Cohen’s effect size d = 0.61 based on the means and 
standard deviations of pleasantness rating changes in our previous study of naloxone versus 
saline [9], statistical power of 80%, and Type I error probability α=0.05.  The effect size of 0.61 
is clinically important for the pleasantness rating outcome. We expect a 20% dropout rate of 
participants based on prior NIH studies. Thus, we will enroll up to 30 participants and dropouts 
will be replaced. 
11. Human Subjects Protection 
 
a. 
Subject selection 
Accrual will be equitable among the participants eligible for this study.  
b. Justification for exclusion of children  
 
The current study constitutes initial research into the affective mechanisms of light stroking and 
deep pressure touch and involves procedures such as intravenous drug infusion that are likely to 
not be well tolerated by children, with no particular benefit to them. In addition, there is evidence 
that affective touch perception differs by age, both in perception and in brain processing, with 
children and older adults differing from young and middle-aged adults [47, 48] which would add 
significant variability to the data.  A separate, age-specific study in children is thus warranted 
and preferable and children will not be included in the current study. 
 

 
 
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c. 
Justification for exclusion of other vulnerable subjects  
 
Participants who do not speak English will not be enrolled because our complete set of 
questionnaires is only validated in English. 
Individuals without consent capacity will be excluded because the research question can be 
answered by enrolling only adults who can consent, and participation does not offer the potential for 
important clinical benefit. Therefore, the risk outweighs the benefit in this population. 
 
Pregnant women and lactating women are excluded because pregnancy and lactation 
significantly alter a women’s hormonal profile and hormones affect touch processing [49, 50], 
and because MRI is contraindicated for pregnancy.  
 
Individuals weighing more than 550 lbs. will be excluded because of the weight limit of the MRI 
scanner.  
 
Because older adults have elevated pain thresholds for brief pain stimuli [51] and there is no 
evidence that their discriminative functions are unchanged, we are excluding people over 50 
years of age. 
 
We will include only right-handed individuals because of increased variability in the 
lateralization of functions in left-handers, including asymmetries in representations of sensory 
function [52]. 
 
 
d. Justification for sensitive procedures  
 
N/A 
 
e. 
Safeguards for vulnerable populations and sensitive procedures  
 
For all fMRI experiments, pregnant women will be excluded from participation due to the 
unknown effects of the high magnetic field on the developing fetus. 
While NCCIH employees are excluded from participation, NIH employees and staff may 
also be considered vulnerable. Protections for employees and staff participating in this study 

 
 
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include 1) assuring that the participation or refusal to participate will have no effect, either 
beneficial or adverse, on the subject’s employment or position at the NIH, 2) giving employees 
and staff who are interested in participating the “NIH Information Sheet on Employee Research 
Participation” prior to obtaining consent, and 3) assuring that there will be no direct solicitation 
of employees or staff. This study collects sensitive information on drug use and alcohol use and 
specific medical diagnoses. The PI will train study staff regarding obtaining and handling 
potentially sensitive and private information about co-workers through staff discussions and 
written branch/section procedures.  Prior to enrollment, potential participants will be informed 
that this sensitive information will be in their NIH medical record. 
 
 
12. Anticipated Benefit 
The study does not offer direct benefit to participants. However, findings from these studies will 
contribute to a mechanistic understanding of affective touch, with potential implications for 
chronic pain. 
14. Consent Documents and Process 
 
 
a. 
Consent procedures  
 
Informed consent for this study will be obtained in-person at the initial visit or during a separate 
visit prior to Session 1, after the initial inclusion criteria have been met via the telephone 
interview and prior to the medical exam or any experimental procedure. The participants will 
have an opportunity to carefully review the consent and ask questions regarding this study prior 
to signing, and they will be informed that they may withdraw from the study at any time without 
prejudice to themselves. The consent procedures will be conducted in a private room by a 
qualified study investigator. All participants will receive a verbal explanation in terms suited to 
their comprehension of the purposes, procedures and potential risks of the study and of their 
rights as research participants. Participants will have the opportunity to carefully review the 
written consent form and ask questions regarding this study prior to signing. NIH employees will 

 
 
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not be consented by a coworker.  
 
b. Consent documents 
 
The consent form contains all required elements. The consent document is submitted with this 
protocol. 
15. Data and Safety Monitoring 
 
a. 
Data and safety monitor 
 
The Principal Investigator will be responsible for monitoring data and safety. 
 
b. Data and safety monitoring plan 
The Principal Investigator is responsible for maintaining adequate clinical records documenting the 
medical history, condition and test results for each study participant throughout the study. Source 
documentation may consist of written or electronic records and supporting data maintained by the 
PI and/or the institution. The medical records for each participant shall document that informed 
consent was obtained prior to participation in the study. 
Dr. Bushnell will review progress of the study annually. Adverse events data will be reviewed as 
they arise to ascertain whether or not there are safety concerns with study procedures. 
 
c. 
Criteria for stopping the study or suspending enrollment or procedures 
 
If there is any serious adverse event (SAE) related to the research, the study will halt until the 
adverse event and a plan to address the SAE has been resolved by the investigator, clinical 
director, and the IRB.  
16. Quality Assurance 
 
a. 
Quality assurance monitor 
The Principal Investigator is responsible for monitoring the quality assurance of this protocol.  
        b.     Quality assurance plan 

 
 
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On a monthly basis, the PI will review all regulatory and patient information with the study team to 
ensure data and study integrity are maintained. Data collected on prepared questionnaire forms will 
be entered into a database against the original source and checked by someone other than the initial 
person entering data. In addition, this protocol will undergo audits by the QA audit committee as 
outlined in the NINDS QA Standard Operating Procedure. For studies greater than minimal risk, 
auditing is conducted in the first year followed by audits q3 year (every third year).  The purpose of 
the QA audit is to assess compliance with applicable regulatory requirements and good clinical 
practice guidelines, as well as to provide recommendations for improving the management of 
clinical research data. 
17. Reporting of Unanticipated Problems, Adverse Events and 
Protocol Deviations 
 
Reportable events for this protocol will be tracked and reported in compliance with policy 801. 
18. Alternatives to Participation  
Subjects do not receive any treatment in this study or forego any treatment in order to participate 
in this study. The alternative, therefore, is not to participate.  
19. Privacy 
 
All research activities will be conducted in as private a setting as possible. 
20. Confidentiality 
 
a. 
For research data and investigator medical records 
 
• We will actively protect confidentiality of the subjects and the data at each step. All medical 
records and subject data will be kept confidential and will only be reviewed by the participating 
investigators.  Data will be de-identified and stored using codes that we assign. De-identified 
data will be kept in encrypted password-protected NCCIH computers in rooms that are locked 

 
 
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when not occupied. Hard copy records/data will be kept in locked cabinets in rooms that are 
locked when not occupied.  Only study investigators will have access to the data. 
• Research staff will be trained by the PI to respect the privacy and confidentiality of NIH 
employees and staff, especially with regard to sensitive, private information.  All data will be de-
identified and personnel will not view data alongside identifying information, which will reduce 
the possibility that lab personnel would be able to associate sensitive information with 
individuals.  The lab will discuss professionalism and confidentiality, and if lab personnel are 
acquainted with any potential participants, a different investigator will interact with that 
participant.  
 
b. For stored samples 
 
Samples will not be stored.  All samples (e.g., urine samples for pregnancy tests and drug 
screens) will be destroyed. 
 
21. Conflict of Interest 
 
a. 
Distribution of NIH guidelines 
 
NIH guidelines on conflict of interest have been distributed to all investigators.   
 
b. 
Conflict of interest  
 
There are no conflicts of interest to report for NIH investigators. 
 
c.  Role of a commercial company or sponsor  
 
N/A 
22. Technology Transfer 
 
No technology transfer agreement is in place for this protocol. 
23. Research and Travel Compensation  
 

 
 
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Subjects will be compensated for time and research-related inconveniences (see table below) on 
an hourly basis. If a session cannot be completed due to unforeseen circumstances (e.g., technical 
issues), payment will be prorated and testing will continue in a rescheduled session.  NIH 
employees and staff who participate during work hours must have permission from their 
supervisor. NIH employees must either participate outside of work hours or take leave in order to 
receive compensation. Payment will be made at the completion of each session. No 
compensation will be made for travel. No escort fees will be provided. The Table below provides 
the compensation matrix that will be used for research compensation: 
 
 
 
 
 
 
 
24. References 
 
 
 
1. 
Gordon, I., et al., Brain mechanisms for processing affective touch. Human Brain 
Mapping, 2013. 34(4): p. 914-922. 
2. 
Ackerley, R., et al., Human C-tactile afferents are tuned to the temperature of a skin-
stroking caress. The Journal of Neuroscience, 2014. 34(8): p. 2879-2883. 
3. 
Löken, L.S., et al., Coding of pleasant touch by unmyelinated afferents in humans. Nature 
neuroscience, 2009. 12(5): p. 547-548. 
4. 
Meller, R.E., E. Keverne, and J. Herbert, Behavioural and endocrine effects of naltrexone 
in male talapoin monkeys. Pharmacology Biochemistry and Behavior, 1980. 13(5): p. 
663-672. 
Consent (if on separate visit, otherwise part 
of hourly rate below) 
Study session (sensory testing with MRI) 
$25 
 
$50 per hour, maximum $300 per session 
Maximum total compensation 
$625 

 
 
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5. 
Fabre-Nys, C., R.E. Meller, and E. Keverne, Opiate antagonists stimulate affiliative 
behaviour in monkeys. Pharmacology Biochemistry and Behavior, 1982. 16(4): p. 653-
659. 
6. 
Schino, G. and A. Troisi, Opiate receptor blockade in juvenile macaques: Effect on 
affiliative interactions with their mothers and group companions. Brain research, 1992. 
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7. 
Martel, F.L., et al., Effects of opioid receptor blockade on the social behavior of rhesus 
monkeys living in large family groups. Developmental psychobiology, 1995. 28(2): p. 71-
84. 
8. 
Graves, F.C., K. Wallen, and D. Maestripieri, Opioids and attachment in rhesus macaque 
(Macaca mulatta) abusive mothers. Behavioral neuroscience, 2002. 116(3): p. 489. 
9. 
Case, L.K., et al., Touch perception altered by chronic pain and by opioid blockade. 
eneuro, 2016. 3(1): p. ENEURO. 0138-15.2016. 
10. 
Loseth, G.E., D.-M. Ellingsen, and S. Leknes, State-dependent μ-opioid modulation of 
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11. 
Mendelson, J.H., et al., Effects of naltrexone on mood and neuroendocrine function in 
normal adult males. Psychoneuroendocrinology, 1978. 3(3): p. 231-236. 
12. 
Schull, J., H. Kaplan, and C.P. O’Brien, Naloxone can alter experimental pain and mood 
in humans. Physiological Psychology, 1981. 9(3): p. 245-250. 
13. 
Grevert, P., et al., Effects of eight-hour naloxone infusions on human subjects. Biological 
psychiatry, 1983. 
14. 
Mense, S. and H. Meyer, Different types of slowly conducting afferent units in cat 
skeletal muscle and tendon. The Journal of Physiology, 1985. 363(1): p. 403-417. 
15. 
Krauss, K.E., The effects of deep pressure touch on anxiety. American Journal of 
Occupational Therapy, 1987. 41(6): p. 366-373. 
16. 
Karlson, C.W., N.A. Hamilton, and M.A. Rapoff, Massage on experimental pain in 
healthy females: A randomized controlled trial. Journal of health psychology, 2014. 
19(3): p. 427-440. 
17. 
Field, T., M. Diego, and M. Hernandez-Reif, Moderate pressure is essential for massage 
therapy effects. International Journal of Neuroscience, 2010. 120(5): p. 381-385. 
18. 
Diego, M.A., et al., Massage therapy of moderate and light pressure and vibrator effects 
on EEG and heart rate. International Journal of Neuroscience, 2004. 114(1): p. 31-44. 
19. 
Field, T., M. Diego, and M. Hernandez-Reif, Massage therapy research. Developmental 
Review, 2007. 27(1): p. 75-89. 
20. 
Perlman, A.I., et al., Massage therapy for osteoarthritis of the knee: a randomized dose-
finding trial. PLoS One, 2012. 7(2): p. e30248. 
21. 
El-Sobky, A., J.O. Dostrovsky, and P.D. Wall, Lack of effect of naloxone on pain 
perception in humans. 1976. 
22. 
Stacher, G., et al., Naloxone does not alter the perception of pain induced by electrical 
and thermal stimulation of the skin in healthy humans. Pain, 1988. 34(3): p. 271-276. 
23. 
Grevert, P. and A. Goldstein, Endorphins: naloxone fails to alter experimental pain or 
mood in humans. Science, 1978. 199(4333): p. 1093-1095. 
24. 
Posner, J. and C. Burke, The effects of naloxone on opiate and placebo analgesia in 
healthy volunteers. Psychopharmacology, 1985. 87(4): p. 468-472. 
25. 
Levine, J., et al., The narcotic antagonist naloxone enhances clinical pain. Nature, 1978. 

 
 
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26. 
Levine, J.D., N.C. Gordon, and H.L. Fields, Naloxone dose dependently produces 
analgesia and hyperalgesia in postoperative pain. 1979. 
27. 
Gracely, R.H., et al., Placebo and naloxone can alter post-surgical pain by separate 
mechanisms. 1983. 
28. 
Anderson, W.S., et al., Naloxone increases pain induced by topical capsaicin in healthy 
human volunteers. Pain, 2002. 99(1): p. 207-216. 
29. 
Frederickson, R.C., V. Burgis, and J.D. Edwards, Hyperalgesia induced by naloxone 
follows diurnal rhythm in responsivity to painful stimuli. Science, 1977. 198(4318): p. 
756-758. 
30. 
Coderre, T.J. and G.B. Rollman, Naloxone hyperalgesia and stress-induced analgesia in 
rats. Life sciences, 1983. 32(18): p. 2139-2146. 
31. 
Kayser, V., J.M. Besson, and G. Guilbaud, Paradoxical effects of low doses of naloxone 
in experimental models of inflammatory pain. Progress in brain research, 1988. 77: p. 
301-312. 
32. 
Lutfy, K. and N.T. Maidment, Blockade of μ‐opioid receptors reveals the hyperalgesic 
effect of orphanin FQ/nociceptin in the rat hot plate test. British journal of 
pharmacology, 2000. 131(8): p. 1684-1688. 
33. 
Price, R.C., et al., Opioid-receptor antagonism increases pain and decreases pleasure in 
obese and non-obese individuals. Psychopharmacology, 2016: p. 1-11. 
34. 
Villemure, C., B.M. Slotnick, and M.C. Bushnell, Effects of odors on pain perception: 
deciphering the roles of emotion and attention. Pain, 2003. 106(1-2): p. 101-8. 
35. 
Essick, G.K., et al., Quantitative assessment of pleasant touch. Neuroscience & 
Biobehavioral Reviews, 2010. 34(2): p. 192-203. 
36. 
Ackerley, R., et al., Touch perceptions across skin sites: differences between sensitivity, 
direction discrimination and pleasantness. Frontiers in behavioral neuroscience, 2014. 8: 
p. 54. 
37. 
Villemure, C. and M.C. Bushnell, Mood influences supraspinal pain processing 
separately from attention. The Journal of Neuroscience, 2009. 29(3): p. 705-715. 
38. 
Wager, T.D., et al., An fMRI-based neurologic signature of physical pain. New England 
Journal of Medicine, 2013. 368(15): p. 1388-1397. 
39. 
Triscoli, C., R. Ackerley, and U. Sailer, Touch Satiety: Differential Effects of Stroking 
Velocity on Liking and Wanting Touch Over Repetitions. 2014. 
40. 
Villemure, C., B.M. Slotnick, and M.C. Bushnell, Effects of odors on pain perception: 
deciphering the roles of emotion and attention. Pain, 2003. 106(1): p. 101-108. 
41. 
Cloninger, C.R., A systematic method for clinical description and classification of 
personality variants: A proposal. Archives of general psychiatry, 1987. 44(6): p. 573-
588. 
42. 
Carver, C.S. and T.L. White, Behavioral inhibition, behavioral activation, and affective 
responses to impending reward and punishment: the BIS/BAS scales. Journal of 
personality and social psychology, 1994. 67(2): p. 319. 
43. 
Zigmond, A.S. and R.P. Snaith, The hospital anxiety and depression scale. Acta 
psychiatrica scandinavica, 1983. 67(6): p. 361-370. 
44. 
Costa, P.T. and R.R. McCrae, The revised neo personality inventory (neo-pi-r). The 
SAGE handbook of personality theory and assessment, 2008. 2: p. 179-198. 
45. 
Wilhelm, F.H., et al., Social anxiety and response to touch: incongruence between self-
evaluative and physiological reactions. Biological psychology, 2001. 58(3): p. 181-202. 

 
 
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46. 
Loggia, M.L., M. Juneau, and M.C. Bushnell, Autonomic responses to heat pain: Heart 
rate, skin conductance, and their relation to verbal ratings and stimulus intensity. 
PAIN®, 2011. 152(3): p. 592-598. 
47. 
Sehlstedt, I., et al., Gentle touch perception across the lifespan. Psychology and aging, 
2016. 31(2): p. 176. 
48. 
Björnsdotter, M., et al., Development of brain mechanisms for processing affective touch. 
Frontiers in behavioral neuroscience, 2013. 8: p. 24-24. 
49. 
Herren, R.Y., The effect of high and low female sex hormone concentration on the two-
point threshold of pain and touch and upon tactile sensitivity. Journal of Experimental 
Psychology, 1933. 16(2): p. 324. 
50. 
Fillingim, R.B. and T. Ness, Sex-related hormonal influences on pain and analgesic 
responses. Neuroscience & Biobehavioral Reviews, 2000. 24(4): p. 485-501. 
51. 
Helme, R., A. Meliala, and S. Gibson, Methodologic factors which contribute to 
variations in experimental pain threshold reported for older people. Neuroscience letters, 
2004. 361(1): p. 144-146. 
52. 
Sörös, P., et al., Cortical asymmetries of the human somatosensory hand representation 
in right-and left-handers. Neuroscience letters, 1999. 271(2): p. 89-92. 
53. 
Oldfield, R.C., The assessment and analysis of handedness: the Edinburgh inventory. 
Neuropsychologia, 1971. 9(1): p. 97-113. 
 
 

 
 
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25. Attachments/ Appendices 
 
Attachment 1: Eligibility Checklist and Pre-Screening Telephone Interview, Pre-Session 
Screening, MINI 
 
Protocol  T-AT-0285________ Telephone Pre-screening 
 
Date of Interview: _____________  Interviewed By: __________________ 
 
Hello, this is (INTERVIEWER) calling from NCCIH.  Is this ______________? Do you have a few minutes to talk 
about our study on the role of opioids in touch? I’d like to give you a brief description of the study, then you can ask 
any questions you may have, and then I’ll have some questions for you.  
 
In this study, we are interested in the role of opioids on the processing of several types of touch sensations. If you 
are eligible and choose to participate, you will be scheduled two test sessions. These sessions will occur at least one 
day apart from each other. During these sessions you will receive naloxone on one day and saline on the other.  
Naloxone is a drug that temporarily blocks your body’s own opioids.  The drugs will be given to you intravenously. 
You will then have an MRI scan and you will receive touch on your leg while under the effects of the drug 
administered that day.  You will be asked to wear shorts or change into scrubs for each session in order to access the 
lower leg. 
 
During the sensory testing, you will experience light touch with a soft brush, pressure with an inflatable leg wrap, 
and heat pain sensations using a thermode. The heat you experience will be painful but tolerable. Your skin will not 
be burned or damaged. You will be asked to provide ratings for the intensity, pain, pleasantness, wanting and liking 
of each of these sensations as well as ongoing ratings of your mood and anxiety.  
 
The MRI will take up to about 75 minutes. People who are afraid of confined spaces may be anxious in the scanner, 
and those with back pain may experience discomfort from lying on the scanner surface. The scanner is loud enough 
to damage hearing, so you will be fitted with hearing protection.  
 
Naloxone, one of the drugs you will receive, is commonly used to reverse the effects of opiates.  It has not been 
shown to produce tolerance or dependence. Most of the associated risks are related to the withdrawal symptoms 
experienced by those with an opioid dependence.  The most common risks reported post-operation are nausea and 
vomiting, reversal of pain relief, agitation, and changes in blood pressure. However, in studies similar to ours, the 
only reported side effects are dry mouth and dizziness. 
 
Your urine will be tested for illegal drugs before each study session. If your drug test is positive, you will not be 
included in the present study. The results of the drug testing will be noted in your NIH medical record. If you do not 
want this information in your medical record, you should not participate in this study. In addition to this drug 
screening, participants who are able to become pregnant will have a pregnancy test. If positive, you will not be able 
to participate because it is unknown if MRI scanning is safe for a developing fetus. We will also document the date 
of onset of your recent menstrual cycle. 
 
Do you have any questions for me about the study? Are you still interested in participating? 
 
□ YES  
□ NO 
 
IF YES: Before I schedule you for a screening visit, I will ask questions to verify that you are eligible to 
participate. Please answer honestly so that we can determine whether it is safe to include you in our study. You 
don’t have to answer questions that you do not feel comfortable answering. All information you provide will remain 
confidential and, if for some reason you cannot participate, all the information collected will be destroyed. 
 
Subject’s Information: 
1. Last name: ___________________________ First name: _____________________________ 

 
 
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2. Address: _________________________________ City: ________________ Zip: __________ 
3. Best Tel: ___________________________ Email: __________________________ 
4. DOB (mm/dd/yyyy): _____/_____/______       
5. Weight ________ (lbs) height: ______      
5. Sex:  
□ M  □ F 
 
VERIFYING INCLUSION CRITERIA  
CRITERIA 
ANSWER 
INCLUDE 
IF 
Can you read and speak English easily (fluent in English)? 
□ YES      □ 
NO 
YES 
What is your age? 
 
18≤ or ≤50 
Are you able to provide written informed consent? 
□ YES     □ NO 
YES 
Administer Edinburgh Handedness Inventory [53]. Right-
handed? 
Right □  Left □ 
Right 
 
VERIFYING EXCLUSION CRITERIA 
CRITERIA 
ANSWER 
EXCLUDE 
IF 
Weight 551 lbs or higher? 
□ YES       □ NO 
YES 
Do you have a congenital limb deficiency or amputation of a 
leg? 
□ YES       □ NO 
YES 
Have you used recreational drugs in the past month (e.g., 
marijuana, MDMA [“ecstasy” or “molly”], LSD, cocaine, 
methamphetamine, heroin, prescription and/or opioids)? 
□ YES       □ NO 
YES 
Are you pregnant or breastfeeding? 
□ YES       □ NO 
YES 
Are you able to comply with the study procedures and visits? 
This includes the ability to schedule a second session within 14 
days of the first session. 
□ YES       □ NO 
NO 
Have you had any dermatological conditions (such as a scar, 
burn, or tattoo) in the testing region in the last four weeks that 
might influence the sensitivity of your skin? Any known nerve 
damage? Any skin area with numbness, prickling/tingling, 
changed sensitivity to touch or temperature, decreased sense of 
vibration? 
□ YES       □ NO 
YES 
Do you currently suffer from chronic pain or have you suffered 
from chronic pain in the past year (pain lasting more than 6 
months) or do you have ongoing treatment with medications for 
neuropathic pain (e.g. gabapentin, tricyclic antidepressants, 
pregabalin, tramadol) 
□ YES      □ NO 
YES 
You must be able to lie comfortably flat on your back for up to 
75 minutes in the MRI scanner. Do you have claustrophobia or 
are you uncomfortable in small closed spaces? 
□ YES      □ NO 
YES 
Do you have a chronic systemic disease (e.g. diabetes)? 
□ YES      □ NO 
YES 

 
 
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Have you ever been diagnosed with major depression, an 
anxiety disorder, substance or alcohol dependence or abuse, 
post-traumatic stress syndrome, bipolar disorder, psychosis, 
attention-deficit/hyperactivity disorder or attempted suicide? Or 
do you have ongoing treatment with medications for any of the 
above (e.g. Selective serotonin reuptake inhibitors (SSRIs), 
Serotonin and norepinephrine reuptake inhibitors (SNRIs), 
Tricyclic antidepressants (TCA), Monoamine oxidase inhibitors 
(MAOs), Benzodiazepines, Anti-epileptic drugs (AEDs), 
Hydroxyzine (antihistamine), Antipsychotics, Disulfiram, 
Varenicline, central stimulants such as Methylphenidate). 
□ YES       □ NO 
YES (if 
current/lifet
ime 
according 
to MINI) 
Do you have a major medical condition such as kidney, liver, 
pulmonary, autonomic, cardiovascular (e.g. blood clots, 
hypertension, preexisting cardiac arrhythmia), or neurological 
disease (e.g., seizure disorder)?  
□ YES       □ NO 
Circle which one 
YES 
Do you currently, or have you ever, had blood clots in your leg? □ YES       □ NO 
Yes 
Do you have any metal in your body that would make having an 
MRI scan unsafe? This includes pacemakers, medication 
pumps, aneurysm clips, shrapnel fragments, permanent eye 
liner, or small metal fragments in the eye that other metal 
workers may have. 
□ YES       □ NO 
YES 
How many alcoholic beverages do you consume each week? 
A "standard" drink according to the NIAAA website 
http://rethinkingdrinking.niaaa.nih.gov/whatcountsdrink/whatsa
standarddrink.asp is any drink that contains about 0.6 fluid ounces or 
14 grams of "pure" alcohol. This corresponds to: 
12 fl oz regular beer (5%) 
8-9 fl oz malt beverage (7%) 
5 fl oz wine (12%) 
3-4 fl oz fortified wine such as sherry, port (17%) 
2-3 fl oz cordial liquor or aperitif (24%) 
1.5 fl oz brandy (40%) 
1.5 fl oz shot or 80-proof spirit (hard liquor) (40%) 
 
 
 
Regular beer: 
Strong beer: 
Wine: 
Fortified wine: 
Cordial Liquor: 
Brandy-like: 
Shots/hard 
liquor: 
 
 
 
Women: > 
7  
 
Men: > 14 
 
 
Are you an NIH employees who is subordinate, a relative, or 
co-worker of any of the investigators, or are you an NCCIH 
DIR employee? 
□ YES       □ NO 
YES 
Do you have allergies to naloxone or similar drugs? 
□ YES       □ NO 
YES 
Do you use any medications that may affect opioid pathways 
(e.g. loperamide or dextromethorphan), could potentially 
interact with naloxone (naltrexone, methylnaltrexone, 
droperidol, fenfluramine and clonidine)  
□ YES       □ NO 
YES 
Do you use any herbal preparations (such as yohimbine)? 
□ YES       □ NO 
YES 
 
 
 
 
 

 
 
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EVALUATION OF MEDICATION USE 
Have you taken any medication in the last 30 days other than over-the-counter NSAIDs or 
acetaminophen, including OTC, RX, topical pain-relieving creams? 
Medication / 
Treatment 
Indication 
Dosage/ 
Interval 
Start 
Date 
End 
Date 
Comments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
If unclear: Thank you. I’ll discuss this information with my team to make sure you’re a good match for 
our study and I’ll contact you soon. 
 
Date of follow up call: (mm/dd/yyyy): _____/_____/______; Time: _____ AM/PM  
 
If not eligible:  Unfortunately, it doesn’t look like this study is a good match for you. I am going to shred 
the information you gave me. If you’d like to find other studies that might be a better match, you can get 
in touch with the clinical recruiting office or go online to Clinicaltrials.gov (If exclude, log and shred) 
 
If eligible: It looks like you would be a good match for our study. I’d like to go ahead and schedule you 
for your first visit.  
 
If they’re new add: “You will need to go through a separate admissions process with the NIH before your 
begin your visit with us and that can take anywhere between 15 minutes and an hour depending on how 
many other people are there that day.”  
 
☐ Discussed communication for 
scheduling. 
Prefers (circle one): Phone        Email 
☐ Would you like me to send you: the 
consent form, map/directions, 
appointment confirmation? 
         
☐ Discussed compensation  
• 
Study session (Sensory testing with MRI): 
$150 each, $300 total for study 
☐ Explained transportation 
Transportation will not be reimbursed but free 
parking is available (validation). 
☐ Updated enrollment log and assigned 
subject code 
 
 
SCHEDULE SESSION 1 ___________; Time: _____  
REMINDER: If you consume alcohol or use pain medications or pain-relieving creams on the 
testing area in the 24 hours prior to your session, we will need to reschedule your session. We will 
email or call you the day before your appointment. Please contact me if you have any questions 
between now and your appointment 

 
 
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In-Person Screening Form 
 
Subject ID: __________________       
 
 
Date _________________ 
 
Session 1 
If participant answers YES to one or more questions below, they will be rescheduled up to two 
times rather than excluded (participants with positive pregnancy tests will be excluded, 
however). If the participant is found non-compliant, i.e., answered YES to one or more questions 
below, during the second rescheduled appointment, he or she will be excluded from the study.  
All eligibility criteria will also be reviewed and confirmed by a LHP. 
 
 
 
 
 
 
 
 
 
 
 
 
CRITERIA 
ANSWER 
RESCHEDULE 
EXCLUDE IF 
Drug test (tox screen) 
□ POS     □ NEG 
POS 
Pregnancy test (those able to become pregnant) 
□ POS     □ NEG 
 YES 
In the last 24 hours, have you consumed alcohol? 
□ YES      □ NO 
YES 
Is the participant showing behavioral signs of 
intoxication? 
• Speech: overly talkative, argumentative, 
opinionated or interrupting; stumbling over words; 
loud, inappropriate language or jokes 
• Coordination: slowed or delayed reactions, 
stagger, swagger, or sway 
• Appearance: vacant or blank expression, smell of 
alcohol on breath, untidy appearance 
• Behavior: overly friendly or withdrawn, 
inappropriate or risky actions, attention difficulties 
□ YES      □ NO 
YES 
Is the participant showing signs of alcohol withdrawal 
syndrome (e.g. symptoms of hand tremors, irregular heart 
rate, fever, nausea, sweating, dehydration, headache, or 
confusion)?  
□ YES      □ NO 
YES 
In the last 24 hours, have you used a topical pain-relieving 
cream (e.g. methylsalicylate, capsaicin) on your arms? 
□ YES      □ NO 
YES 
In the last 3 days, have you used any non-steroidal anti-
inflammatory drug (NSAID) and/or over-the-counter drug 
(e.g., aspirin, ibuprofen, acetaminophen, naproxen)? 
□ YES      □ NO 
YES 
 
SCHEDULE SESSION 2 ___________; Time: _____  
REMINDER: If you consume alcohol or use pain medications or pain-relieving creams on the 
testing area in the 24 hours prior to your session, we will need to reschedule your session. We will 
email or call you the day before your appointment. Please contact me if you have any questions 
between now and your appointment 
 
Session 2 

 
 
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All eligibility criteria will also be reviewed with an LHP to confirm there are no changes. 
CRITERIA 
ANSWER 
RESCHEDULE 
IF 
Drug test (tox screen) 
□ POS     □ NEG 
POS 
Pregnancy test (those able to become pregnant) 
□ POS     □ NEG 
EXCLUDE 
In the last 24 hours, have you consumed alcohol? 
□ YES      □ NO 
YES 
Is the participant showing behavioral signs of 
intoxication? 
• Speech: overly talkative, argumentative, 
opinionated or interrupting; stumbling over words; 
loud, inappropriate language or jokes 
• Coordination: slowed or delayed reactions, 
stagger, swagger, or sway 
• Appearance: vacant or blank expression, smell of 
alcohol on breath, untidy appearance 
• Behavior: overly friendly or withdrawn, 
inappropriate or risky actions, attention difficulties 
□ YES      □ NO 
YES 
Is the participant showing signs of alcohol withdrawal 
syndrome (e.g. symptoms of hand tremors, irregular heart 
rate, fever, nausea, sweating, dehydration, headache, or 
confusion)?  
□ YES      □ NO 
YES 
In the last 24 hours, have you used a topical pain-relieving 
cream (e.g. methylsalicylate, capsaicin) on your arms? 
□ YES      □ NO 
YES 
In the last 3 days, have you used any non-steroidal anti-
inflammatory drug (NSAID) and/or over-the-counter drug 
(e.g., aspirin, ibuprofen, acetaminophen, naproxen, 
sumatriptan)? 
□ YES      □ NO 
YES 
 
If any of the questions regarding behavioural signs of intoxication or signs of alcohol withdrawal 
are answered YES the subject should be immediately excluded and not rescheduled. 
 
If one or more other question answers are YES: 
Is this the first or second time the participant will be rescheduled? (circle one) 
 
Rescheduled Appointment:   
Date (mm/dd/yyyy): _____/_____/______  Time: _____ AM/PM 
 
 
 
 
 
 
 
 
 

 
 
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Attachment 2: Rating Scales, and Questionnaires: TCI, HADS, BI/BAS, NEO-FFI-3, STQ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
-100 
100 
0 
MOOD 
EXTREMELY BAD 
EXTREMELY GOOD 
NEUTRAL 
100 
0 
-100 
100 
0 
UNPLEASANTNESS/PLEASANTNESS 
EXTREMELY 
UNPLEASANT 
EXTREMELY 
PLEASANT 
NEUTRAL 
-100 
100 
0 
WANTING 
NOT AT ALL 
VERY MUCH 
NEUTRAL 
-100 
ANXIETY 
EXTREMELY 
ANXIOUS 
EXTREMELY CALM 
NEUTRAL 
-100 
100 
0 
INTENSITY 
NO SENSATION  
INTOLERABLE 
PAIN  
PAIN THRESHOLD 

 
 
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Temperament and Character Inventory 
TCI 
 
How to fill out this questionnaire 
 
To answer you only need to circle either “T”  (True) or “F”  (False) after each question.  
 
Read each statement carefully, but don’t spend too much time deciding on the answer.  
 
Please answer every statement, even if you are not completely sure of the answer.  
 
Remember that there are no right or wrong answers – just describe you own personal opinions 
and feelings. 
 
 
 
 
 
 
True 
False 
1. 
(1) 
I often try new things just for fun or thrills, even if 
most people think it is a waste of time. 
 
T 
F 
2. 
(2) 
I usually am confident that everything will go well, 
even in situations that worry most people. 
 
T 
F 
3. 
(3) 
I am often moved deeply by a fine speech or poetry. 
 
T 
F 
4. 
(11) 
I could probably accomplish more than I do, but I 
don’t see the point in pushing myself harder than is 
necessary to get by. 
 
T 
F 
-100 
100 
0 
LIKING 
NOT AT ALL  
 VERY MUCH 
NEUTRAL 

 
 
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5. 
(12) 
I often feel tense and worried in unfamiliar situations, 
even when others feel there is little to worry about. 
 
T 
F 
6. 
(13) 
I often do things based on how I feel at the moment 
without thinking how they were done in the past. 
 
T 
F 
7. 
(14) 
I usually do things my own way – rather than giving 
in to the wishes of other people. 
 
T 
F 
8. 
(19) 
I am much more reserved and controlled than most 
people. 
 
T 
F 
9. 
(20) 
I often have to stop what I am doing because I start 
worrying about what might go wrong. 
 
T 
F 
10. 
(21) 
I like to discuss my experiences and feelings openly 
with friends instead of keeping them to myself. 
 
T 
F 
11. 
(22) 
I have less energy and get tired more quickly than 
most people. 
 
T 
F 
12. 
(26) 
Most of the time I would prefer to do something a 
little risky (like riding in an automobile over steep 
hills and sharp turns) – rather than having to stay quiet 
and inactive for a few hours. 
 
T 
F 
13. 
(27) 
I often avoid meeting strangers because I lack 
confidence with people I do not know. 
 
T 
F 
14. 
(28) 
I like to please other people as much as I can. 
 
 
T 
F 
15. 
(29) 
I like old “tried and true” ways of doing things much 
better than trying “new and improved” ways. 
 
T 
F 
16. 
(34) 
I like to be very organized and set up rules for people 
whenever I can. 
 
T 
F 
17. 
(35) 
It is difficult for me to keep the same interests for a 
long time because my attention often shifts to 
something else.  
 
T 
F 
18. 
(37) 
I am usually so determined that I continued to work 
long after other people have given up. 
 
T 
F 

 
 
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19. 
(41) 
I often spend money until I run out of cash or get into 
debt from using too much credit. 
 
T 
F 
20. 
(42) 
I think I will have very good luck in the future. 
 
T 
F 
21. 
(43) 
I recover more slowly than other people from minor 
illnesses or stress. 
 
T 
F 
22. 
(44) 
It wouldn’t bother me to be alone all the time. 
 
T 
F 
23. 
(46) 
I don’t care very much whether other people like me 
or the way I do things. 
 
T 
F 
24. 
(52) 
In conversations I am much better as a listener than as 
a talker. 
 
T 
F 
25. 
(53) 
I lose my temper more quickly than most people. 
 
T 
F 
 
26. 
 
(54) 
 
When I have to meet a group of strangers, I am more 
shy than most people. 
 
T 
F 
27. 
(55) 
I am more sentimental than most people. 
 
T 
F 
28. 
(61) 
I like to think about things for a long time before I 
make a decision. 
 
T 
F 
29. 
(62) 
I am more hard-working than most people. 
 
T 
F 
30.  
(63) 
I often need naps or extra rest periods because I get 
tired so easily. 
 
T 
F 
31. 
(65) 
Regardless of any temporary problem that I have to 
overcome, I always think it will turn out well. 
T 
F 
32. 
(66) 
It is hard for me to enjoy spending money on myself, 
even when I have saved plenty of money. 
 
T 
F 
33. 
(67) 
I usually stay calm and secure in situations that most 
people would find physically dangerous. 
 
T 
F 
34. 
(68) 
I like to keep my problems to myself 
 
T 
F 
35. 
(70) 
I like to stay at home better than to travel or explore 
new places. 
 
T 
F 

 
 
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36. 
(71) 
I do not think it is smart to help weak people who 
cannot help themselves. 
 
T 
F 
37. 
(79) 
I like it when people can do whatever they want 
without strict rules and regulations. 
 
T 
F 
38. 
(80) 
I would probably stay relaxed and outgoing when 
meeting a group of strangers, even if I were told they 
are unfriendly. 
 
T 
F 
39. 
(81) 
Usually I am more worried than most people that 
something might go wrong in the future. 
 
T 
F 
40. 
(82) 
I usually think about all the facts in detail before I 
make a decision. 
 
T 
F 
41. 
(83) 
I feel it is more important to be sympathetic and 
understanding of other people than to be practical and 
tough-minded 
T 
F 
42. 
(91) 
I am usually able to get other people to believe me, 
even when I know that what I am saying is 
exaggerated or untrue. 
 
T 
F 
43. 
(92) 
I need much extra rest, support, or reassurance to 
recover from minor illnesses or stress. 
 
T 
F 
44. 
(99) 
I have a reputation as someone who is very practical 
and does not act on emotion. 
 
T 
F 
45. 
(100) It is easy for me to organize my thoughts while 
talking to someone. 
 
T 
F 
46. 
(102) I am strongly moved by sentimental appeals (like 
when asked to help crippled children) 
T 
F 
47. 
(103) I usually push myself harder than most people do 
because I want to do as well as I possibly can. 
 
T 
F 
48. 
(108) I hate to make decisions based only on my first 
impressions. 
 
T 
F 
49. 
(109) I prefer spending money rather than saving it. 
 
T 
F 
50. 
(110) I can usually do a good job of stretching the truth to 
tell a funnier story or to play a joke on someone. 
 
T 
F 

 
 
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51. 
(112) If I am embarrassed or humiliated, I get over it very 
quickly. 
 
T 
F 
52. 
(113) It is extremely difficult for me to adjust to change in 
my usual way of doing things because I get so tense, 
tired, or worried. 
 
T 
F 
53. 
(114) I usually demand very good practical reasons before I 
am willing to change my old ways of doing things. 
 
T 
F 
54. 
(117) I would like to have warm and close friends around 
with me most of the time. 
 
T 
F 
55.  
(119) I nearly always stay relaxed and carefree, even when 
nearly everyone else is fearful. 
 
T 
F 
56. 
(120) I find sad songs and movies pretty boring. 
 
T 
F 
57. 
(128) I am satisfied with my accomplishments, and have  
little desire to do better. 
T 
F 
58. 
(129) I often feel tense and worried in unfamiliar situations, 
even when others feel there is no danger at all. 
 
T 
F 
59. 
(130) I often follow my instincts, hunches, or intuition 
without thinking through all the details. 
 
T 
F 
60. 
(131) Other people often think that I am too independent 
because I won’t do what they want. 
 
T 
F 
61. 
(139) I am better at saving money than most people. 
 
T 
F 
62. 
(141) Even when most people feel it is not important, I 
often insist on things being done in a strict and orderly 
way. 
T 
F 
63. 
(142) I feel very confident and sure of myself in almost all 
social situations.  
 
T 
F 
64. 
(143) My friends find it hard to know my feelings because I 
seldom tell them about my private thoughts. 
 
T 
F 
65. 
(144) I hate to change the way I do things, even if many 
people tell me there is a new and better way to do it. 
 
T 
F 
66. 
(147) I am more energetic and tire less quickly than most 
people. 
 
T 
F 

 
 
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67. 
(148) I like to pay close attention to details in everything I 
do. 
 
T 
F 
68. 
(149) I often stop what I am doing because I get worried, 
even when my friends tell me everything will go well. 
 
T 
F 
69. 
(154) Most of the time I would prefer to do something risky 
(like hand-gliding or parachute jumping) – rather than 
having to stay quiet and inactive for a few hours. 
 
T 
F 
70. 
(155) Because I so often spend too much money on impulse, 
it is hard for me to save money – even for special 
plans like a vacation. 
 
T 
F 
71. 
(156) I don’t go out of my way to please other people. 
 
T 
F 
72. 
(157) I am not shy with strangers at all. 
 
T 
F 
73. 
(158) I often give in to the wishes of friends. 
 
T 
F 
74. 
(164) I never worry about terrible things that might happen 
in the future. 
 
T 
F 
75. 
(165) I almost never get so excited that I lose control of 
myself. 
 
T 
F 
76. 
(166) I often give up a job if it takes much longer than I 
thought it would. 
 
T 
F 
77. 
(167) I prefer to start conversations, rather than waiting for 
other to talk to me. 
 
T 
F 
78. 
(174) It is fun for me to buy things for myself. 
 
T 
F 
79. 
(180) I usually like to stay cool and detached from other 
people. 
 
T 
F 
80. 
(181) I am more likely to cry at a sad movie than most 
people. 
 
T 
F 
81. 
(182) I recover more quickly than most people from minor 
illnesses or stress. 
 
T 
F 
82. 
(183) I often break rules and regulations when I think I can 
get away with it. 
 
T 
F 

 
 
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83. 
(187) I like to make quick decisions so I can get on with 
what has to be done. 
 
T 
F 
84. 
(188) I usually have good luck in whatever I try to do. 
 
T 
F 
85. 
(189) I am usually confident that I can do things that most 
people would consider dangerous (such as driving an 
automobile fast on a wet or icy road).  
 
T 
F 
86. 
(191) I like to explore new ways to do things. 
 
T 
F 
87. 
(192) I enjoy saving money more than spending it on 
entertainment or thrills. 
 
T 
F 
88. 
(193) Individual rights are more important than the needs of 
any group. 
 
T 
F 
89. 
(201) Even when I am with friends, I prefer not to “open 
up” very much. 
 
T 
F 
90. 
(202) I usually can stay “on the go” all day without having 
to push myself. 
 
T 
F 
91. 
(203) I nearly always think of all the facts in detail before I 
make a decision, even when other people demand a 
quick decision.  
 
T 
F 
92. 
(204) I am not very good at talking my way out of trouble 
when I am caught doing something wrong. 
 
T 
F 
93. 
(205) I am more of a perfectionist than most people. 
 
T 
F 
94. 
(209) I think I would stay confident and relaxed when 
meeting strangers, even if I were told they are angry at 
me. 
 
T 
F 
95. 
(210) People find it easy to come to me for help, sympathy, 
and warm understanding. 
 
T 
F 
96. 
(211) I am slower than most people to get excited about new 
ideas and activities. 
 
T 
F 
97. 
(212) I have trouble telling a lie, even when it is meant to 
spare someone else’s feeling. 
 
T 
F 

 
 
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98. 
(217) I usually feel tense and worried when I have to do 
something new and familiar. 
 
T 
F 
99. 
(218) I often push myself to the point of exhaustion or try to 
do more than I really can. 
 
T 
F 
100. (219) Some people think I am too stingy or tight with my 
money. 
 
T 
F 
101. (224) I regularly take time to consider whether what I am 
doing is right or wrong. 
 
T 
F 
102. (225) Things often go wrong for me unless I am very 
careful. 
 
T 
F 
103. (226) If I am feeling upset, I usually feel better around 
friends than when left alone. 
 
T 
F 
104. (231) I usually stay away from social situations where I 
would have to meet strangers, even if I am assured 
that they will be friendly. 
T 
F 
105. (236) I usually feel much more confident and energetic than 
most people, even after minor illnesses or stress. 
 
T 
F 
106. (237) I like to read everything when I am asked to sign any 
papers. 
 
T 
F 
107. (238) When nothing new is happening, I usually start 
looking for something that is thrilling or exciting. 
T 
F 
 
 
 

 
 
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Hospital Anxiety and Depression Scale (HADS) 
 
Name _____________________ 
Date _____________________ 
 
 
We would like to know how the following statements currently describe your feelings. 
Please choose one response from the four given for each statement. Give us your 
immediate response and don’t think too long about your answers. Please go 
through all 14 statements and do not miss a statement. 
 
Thank you 
 
1 I feel tense or 'wound up': 
  
  
Most of the time 
  
  
A lot of the time 
  
  
From time to time, occasionally   
  
Not at all 
  
  
2 I still enjoy the things I used to 
enjoy: 
  
  
Definitely as much 
  
  
Not quite so much 
  
  
Only a little 
  
  
Hardly at all 
  
  
3 
I get a sort of frightened 
feeling as if something awful is 
about to happen: 
  
  
Very definitely and quite badly 
  
  
Yes, but not too badly 
  
  
A little, but it doesn't worry me   
  
Not at all 
 

 
 
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4 I can laugh and see the funny 
side of things: 
  
  
As much as I always could 
  
  
Not quite so much now 
  
  
Definitely not so much now 
  
  
Not at all 
  
  
5 Worrying thoughts go through 
my mind: 
  
  
A great deal of the time 
  
  
A lot of the time 
  
  
From time to time, but not too 
often 
  
  
Only occasionally 
  
  
6 I feel cheerful: 
  
  
Not at all 
  
  
Not often 
  
  
Sometimes 
  
  
Most of the time 
  
  
7 I can sit at ease and feel 
relaxed: 
  
  
Definitely 
  
  
Usually 
 
  
Not Often 
  
  
Not at all 
  

 
 
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8 I feel as if I am slowed down: 
  
  
Nearly all the time 
  
  
Very often 
  
  
Sometimes 
  
  
Not at all 
  
  
 
 
9 
I get a sort of frightened 
feeling like 'butterflies' in the 
stomach: 
  
  
Not at all 
  
  
Occasionally 
  
  
Quite Often 
  
  
Very Often 
  
  
 
 
10 I have lost interest in my 
appearance: 
  
  
Definitely 
  
  
I don't take as much care as I 
should 
  
  
I may not take quite as much 
care 
  
  
I take just as much care as ever   
 

 
 
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11 I feel restless as I have to be 
on the move: 
  
  
Very much indeed 
  
  
Quite a lot 
  
  
Not very much 
  
  
Not at all 
  
 
12 I look forward with enjoyment 
to things: 
  
  
As much as I ever did 
  
  
Rather less than I used to 
  
  
Definitely less than I used to 
  
  
Hardly at all 
  
  
13 I get sudden feelings of panic:   
  
Very often indeed 
  
  
Quite often 
  
  
Not very often 
  
  
Not at all 
  
  
14 I can enjoy a good book or 
radio or TV program: 
  
  
Often 
  
  
Sometimes 
  
  
Not often 
  
  
Very seldom 
  
 
 

 
 
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BEHAVIORAL AND APPETITIVE SYSTEM SCALE 
(BIS/BAS) 
 
Each item of this questionnaire is a statement that a person may either agree with or disagree 
with. For each item, indicate how much you agree or disagree with what the item says. Please 
respond to all the items; do not leave any blank. Choose only one response to each statement. 
Please be as accurate and honest as you can be. Respond to each item as it were the only item. 
That is, don’t worry about being “consistent” in your responses. Choose from the following four 
response options: 
 
1 = very true for me  
2 = somewhat true for me 
3 = somewhat false for me 
4 = very false for me 
 
 
1. A person’s family is the most important thing in life. ____ 
2. Even if something bad is about to happen to me, I rarely experience fear or nervousness. 
____  
3. I go out of my way to get things I want. ____ 
4. When I’m doing well at something I love to keep at it. ____ 
5. I’m always willing to try something new if I think it will be fun. ____ 
6. How I dress is important to me. ____ 
7. When I get something I want, I feel excited and energized. ____ 
8. Criticism or scolding hurts me quite a bit. ____ 
9. When I want something I usually go all-out to get it. ____ 
10. I will often do things for no other reason than that they might be fun. ____ 
11. It’s hard for me to find the time to do things such as get a haircut. ____ 
12. If I see a chance to get something I want I move on it right away. ____ 
13. I feel pretty worried or upset when I think or know somebody is angry at me. ____ 
14. When I see an opportunity for something I like I get excited right away. ____ 
15. I often act on the spur of the moment. ____ 
16. If I think something unpleasant is going to happen I usually get pretty “worked up”. ____ 
17. I often wonder why people act the way they do. ____ 
18. When good things happen to me, it affects me strongly. ____ 
19. I feel worried when I think I have done poorly at something important. ____ 
20. I crave excitement and new sensations. ____ 
21. When I go after something I use a “no holds barred” approach. ____ 
22. I have very few fears compared to my friends. ____  
23. It would excite me to win a contest. ____ 
24. I worry about making mistakes. ____ 
 

 
 
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SOCIAL TOUCH QUESTIONNAIRE 
 
 
Indicate how characteristic or true each of the following statements is of you: 
 
0-4 scale (0 = not at all, 1 = slightly, 2 = moderately, 3 = very, 4 = extremely) 
 
 
0 
1 
2 
4 
5 
I generally like when people express their 
affection towards me in a physical way 
 
 
 
 
 
 
I feel uncomfortable when someone I 
don’t know very well hugs me 
 
 
 
 
 
I get nervous when an acquaintance keeps 
holding my hand after a handshake 
 
 
 
 
 
I generally seek physical contact with 
others 
 
 
 
 
 
I feel embarrassed if I have to touch 
someone in order to get their attention 
 
 
 
 
 
I consider myself to be a ‘touchy-feely’ 
person 
 
 
 
 
 
It annoys me when someone touches me 
unexpectedly 
 
 
 
 
 
I’d feel uncomfortable if a professor 
touched me on the shoulder in public 
 
 
 
 
 
I’d be happy to give a neck/shoulder 
massage to a friend if they are feeling 
stressed 
 
 
 
 
 
I feel uncomfortable if I make physical 
contact with a stranger on the bus or 
subway 
 
 
 
 
 
I like being caressed in intimate situations 
 
 
 
 
 

 
 
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As a child, I was often cuddled by family 
members (e.g. parents, siblings) 
 
 
 
 
 
I would rather avoid shaking hands with 
strangers 
 
 
 
 
 
I greet my close friends with a kiss, 
cheek-to-cheek 
 
 
 
 
 
I feel comfortable touching people I do 
not know very well 
 
 
 
 
 
I feel disgusted when I see public displays 
of intimate affection 
 
 
 
 
 
It would make me feel anxious if someone 
I had just met touched me on the wrist 
 
 
 
 
 
If I had the means, I would get weekly 
professional massages 
 
 
 
 
 
I hate being tickled 
 
 
 
 
 
I like petting animals 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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Attachment 3: Precis for clinicaltrials.gov 
Précis: 
 
Objective: Our sense of touch includes the intensity, pleasantness and unpleasantness of touch.  
There is some evidence that opioids affect the perception of touch and that blocking endogenous 
opioid release alters perception of touch and pain.  The current study will examine the role of 
endogenous opioids in the perception of light skin stroking, deep pressure touch, and painful 
heat. Further, it will examine the neural basis of observed perceptual changes, using fMRI. 
 
Study Population: 30 healthy participants will be enrolled in the study. 
Design: Participants will receive intravenous saline or intravenous naloxone on separate days to 
investigate the effect of mu-opioid antagonism on the intensity and pleasantness of superficial 
and deep affective touch and the intensity and unpleasantness of cutaneous heat pain.  Using a 
double-blind cross-over design, functional Magnetic Resonance Imaging (fMRI) will be 
conducted during sensory testing before and after the infusion of each drug to examine the neural 
mediation of opioid effects on touch perception. Ratings of mood, anxiety, pain intensity, 
pleasantness/unpleasantness, wanting and liking will also be collected throughout the study 
session. 
 
Outcome measures: We will compare subjective ratings (mood, calmness, anxiety, 
pleasantness, unpleasantness, wanting, liking, pain intensity and unpleasantness) during 
naloxone and saline to: 1) Determine whether naloxone alters the pleasantness and/or intensity of 
affective touch (light brush and deep compression); 2) Determine whether naloxone alters the 
unpleasantness and/or intensity of cutaneous heat pain; 3) Determine the role of mood or anxiety 
changes in mediating the effect of endogenous opioids on these perceptual measures; 3) 
Determine changes in the brain activation related to these effects. 
 
26. Consent Forms 
Please see separate Consent Form document.