Clinical trial NCT01878006
Conditions: Polymorphism-Genetic Pain Addiction
Keywords: Opiate Receptor Genotype PET Imaging
Sponsor: National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Start date: 2013-06-13; Completion date: 2017-04-27
Enrollment: 15 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
Background:

\- Small differences in genes may alter responses to drugs. One gene that has different forms is the mu opioid receptor gene. People with one form of this gene are more sensitive to alcohol. People with a different form are sometimes more sensitive to pain. Morphine and other prescription pain pills produce pain relief by acting at the mu opioid receptor. Researchers want to see the effect of morphine on brain reward and subjective effects. Morphine is a strong but short-acting pain medication that is sometimes used for anesthesia during surgery.

Objectives:

\- To compare the effect of morphine on brain measures of dopamine release using imaging.

Eligibility:

\- Individuals between 21 and 55 years of age who have previously taken pain pills prescribed to treat pain from a medical or dental procedure.

Design:

* This study has a screening phase and a study phase. The screening phase involves one or two visits of 5 to 6 hours. The study phase consists of 4 study visits. Each study visit will take about 8 hours.
* Participants will be screened with a medical and psychiatric history and physical exam. They will be asked about drinking and drug-taking history, and any family history of alcoholism or drug abuse. Blood, urine, and breath samples will be collected.
* During the first study visit, an MRI scan may be performed, questionnaires completed, and a blood sample collected for genetic testing.
* During study visit 2, participants will test their pain sensitivity by placing one hand in cold water. Pupil diameter will be measured after the sensitivity test. After a blood sample is taken, participants will receive the morphine or a salt solution. The sensitivity test and pupil diameter test will be repeated. Final blood samples will be collected. A brief physical exam will also be performed.
* During study visits 3 and 4, participants will receive morphine or a salt solution during a PET scan. Questionnaires to assess subjective effects will be administered. Final blood samples will be collected. A brief physical exam will also be performed.
* Participants will stay in the clinic until the effects of the drug have worn off after study visits 2, 3, and 4.
* About 1 week after the study session, participants will have a follow-up phone call.

Detailed description:
Objectives

Mesolimbic dopamine (DA) release is a key signal for drug reward, and endogenous opioids are thought to exert their effects in part by modulating the activity of this system. A functional µ-opioid receptor (OPRM1) A118G single nucleotide polymorphism (SNP) has been associated with increased risk for heroin addiction in some studies. This polymorphism has been shown to confer differential pain sensitivity and to alter the release of DA following an alcohol challenge. The objective of this study is to examine the role of the A118G OPRM1 polymorphism for responses to a challenge of an opiate (morphine) with regard to psycho-physiological variables measured in the laboratory and for brain dopamine release measured by \[11C\]raclopride PET.

Study Population

Healthy male participants who have had experience with oral prescription analgesics (e.g., Oxycontin, Vicodin, Percocet, oxycodone) will be recruited for the study. These volunteers will be screened to obtain samples of two groups of subjects: 1) persons homozygous for the major 118A allele (118AA genotype); 2) persons carrying one or two copies of the variant 118G allele (118AG or 118GG genotype, hereafter called 118GX). We will recruit up to 120 participants to obtain 40 completers per genotype for the study.

Design

We will compare the response of these groups to a challenge with morphine given intravenously. Participants will receive a standardized IV challenge of morphine (10.0 mg/70 kg over 1 minute; morphine concentration 2 mg/ml). Pre and post injection measures will be made in two areas: 1) subjective response as measured by standardized questionnaires, and 2) measures of physiological response, including pupil response to light, respiratory rate, oxygen saturation and a pain rating from putting a hand in cold water and blood chemistries. In addition, during this visit, participants will wear the AutoSense mobile physiological monitor; parameters measured by AutoSense include respiration rate, heart rate, heart-rate variability, skin conductance, and activity level. The injection will be repeated in all participants in the PET scanner, once with morphine and once with normal saline. Dopamine release will be assessed by determining the difference between the binding potential for \[11C\]raclopride, a positron emitter labeled ligand which binds preferentially to D2 receptors during saline administration and its binding potential during morphine administration.

Outcome measures

We hypothesize that 118GX subjects will have significantly different subjective response to the challenge than 118AA subjects as observed in participants receiving alcohol in a similar study (Ramchandani et al. 2011). However, the genotype effect on the response may be opposite from the effect of genotype on the alcohol response. We also hypothesize that the PET studies with \[11C\]raclopride will show that 118GX subjects have less dopamine release during morphine administration than 118 AA subjects.

Arms: arm 1: Morphine injection 10 mg/70kg arm 2: Saline injection
Interventions: intervention 1: Morphine intervention 2: Placebo
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_SAP_000.pdf: 
PI name: Vijay A. Ramchandani, Ph.D. 
 
Date:  02/27/2018 
 
Protocol number:  13-AA-0061 
Version:  7.0 
CNS IRB Protocol Template (rev 9.21.11) 
 
 
 
Page 1 of 62 
Protocol Title: OPRM1 A118G SNP Effect on Striatal Dopamine Response to an IV 
Opiate  
Abbreviated Title: Genetics, DA Release & Opiate 
 
Protocol Number:  13-AA-0061  
Date of This Submission/Version: 02/27/2018 Version 7.0 (CR April 2018) 
Principal Investigator 
Name, Degree 
Branch/Institute Bldg/Rm 
Phone 
E-mail 
Vijay A. 
Ramchandani, 
Ph.D. 
LCTS/NIAAA 
10(CRC)/ 
2-2352 
301-
402-
8527 
vijayr@mail.nih.gov 
 
Associate Investigators 
Name, Degree 
Branch/Institute 
Bldg/Rm 
Phone 
E-mail 
Peter 
Herscovitch, 
M.D. 
PET/CC 
10/1C495 
301-451-
4248 
pherscovitch@mail.nih. 
gov 
Kenzie 
Preston, Ph.D. 
CPTRB/NIDA/I
RP 
BRC/01B602 
443-740-
2326 
kpreston@mail.nih.gov 
Elliot Stein, 
Ph.D. 
NRB, NIDA-IRP 
BRC/ 
07A711A 
443-740-
2650 
estein@mail.nih.gov 
Primavera A. 
Spagnolo, 
M.D. 
LCTS/NIAAA 
10(CRC)/1-
5330 
301-827-
0352 
Vera.spagnolo@nih.gov 
Reza 
Momenan, 
Ph.D. 
LCTS/NIAAA   
10-(CRC) 1-
5330 
301-451-
6972   
rezam@nih.gov 
Nancy 
Diazgranados, 
M.D., M.S. 
LCTS/NIAAA 
10(CRC)/1-
5330 
301-496-
7515 
Nancy.diazgranados@ 
nih.gov 
Michelle  
Leff, 
M.D., M.B.A. 
NIDA/IRP/ 
OSD  
 
BRC/ 
02A638A 
 
443-740-
2246  
 
MLeff@intra.nida.nih. 
gov 
 
 
 
Research Contact  
Name, Degree 
Branch/Institute 
Bldg/Rm 
Phone 
E-mail 
Vijay A. 
Ramchandani, 
Ph.D. 
LCTS/NIAAA 
10(CRC)/ 
2-2352 
301-402-
8527 
vijayr@mail.nih.gov 
 
Medical Advisory Investigator 
Name, Degree 
Branch/Institute 
Bldg/Rm 
Phone 
E-mail 
Karran 
Phillips, MD, 
MSc 
CPTRB/NIDA/ 
IRP 
BRC/01B616 
443-740-
2298 
phillipsk@nida.nih.gov 
 


 
 
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Total requested accrual (separately specify planned accrual for each subject group)     
 
  (0) Patients       
  (120) Healthy Volunteers  
  
 
Project Uses Ionizing Radiation:    No  
Yes (attach RSC/RDRC documentation) 
  
 
 Medically-indicated only 
  
 
 Research-related only 
  
 
 Both 
 
IND/IDE 
 
 
 
 No   
Yes (attach FDA documentation) 
  
Drug/Device/# IND 54135 for 11C Raclopride 
  
Sponsor: __ NIH Clinical Center-PET Imaging Dept____ 
 
Durable Power of Attorney  
 
 No   
 Yes  
 
Multi-institutional Project 
 
 No   
 Yes  
 
 
 
 
 
Institution#1_________________    FWA #_________  
Date of IRB approval _____________(attach IRB documentation) 
 
 
Institution#2_________________    FWA #_________  
Date of IRB approval _____________(attach IRB documentation) 
(If NIH is the coordinating site, list each institution; attach documentation of IRB approval for 
each site) 
(If NIH is not the coordinating site, list the coordinating site; attach documentation of IRB 
approval for lead site) 
 
Data and Safety Monitoring Board  
No   
 Yes  
Technology Transfer Agreement  
 No   
 Yes  
Agreement type and number _#30749-10__ Expiration Date_ July 29, 2016___  with 
University of Memphis to cover the AutoSense in the opiate PET study  
Samples are being stored  
 
 
 No   
 Yes  
Flesch-Kincaid reading level of consent form: ___8.6_________  
(exclude boilerplate in assessing reading level)


 
 
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Précis: 
 
Objectives 
Mesolimbic dopamine (DA) release is a key signal for drug reward, and endogenous 
opioids are thought to exert their effects in part by modulating the activity of this system. 
A functional µ-opioid receptor (OPRM1) A118G single nucleotide polymorphism (SNP) 
has been associated with increased risk for heroin addiction in some studies.  This 
polymorphism has been shown to confer differential pain sensitivity and to alter the 
release of DA following an alcohol challenge. The objective of this study is to examine 
the role of the A118G OPRM1 polymorphism for responses to a challenge of an opiate 
(morphine) with regard to psycho-physiological variables measured in the laboratory and 
for brain dopamine release measured by [11C]raclopride PET. 
Study population 
Healthy male participants who have had experience with oral prescription analgesics 
(e.g., Oxycontin, Vicodin, Percocet, oxycodone) will be recruited for the study.  These 
volunteers will be screened to obtain samples of two groups of subjects: 1) persons 
homozygous for the major 118A allele (118AA genotype); 2) persons carrying one or 
two copies of the variant 118G allele (118AG or 118GG genotype, hereafter called 
118GX).  We will recruit up to 120 participants to obtain 40 completers per genotype for 
the study. 
Design  
We will compare the response of these groups to a challenge with morphine given 
intravenously. Participants will receive a standardized IV challenge of morphine (10.0 
mg/70 kg over 1 minute; morphine concentration 2 mg/ml).  Pre and post injection 
measures will be made in two areas: 1) subjective response as measured by standardized 
questionnaires, and 2) measures of physiological response, including pupil response to 
light, respiratory rate, oxygen saturation and a pain rating from putting a hand in cold 
water and blood chemistries. In addition, during this visit, participants will wear the 
AutoSense mobile physiological monitor; parameters measured by AutoSense include 
respiration rate, heart rate, heart-rate variability, skin conductance, and activity level. The 
injection will be repeated in all participants in the PET scanner, once with morphine and 
once with normal saline.  Dopamine release will be assessed by determining the 
difference between the binding potential for [11C]raclopride, a positron emitter labeled 
ligand which binds preferentially to D2 receptors during saline administration and its 
binding potential during morphine administration.  
Outcome measures 
We hypothesize that 118GX subjects will have significantly different subjective response 
to the challenge than 118AA subjects as observed in participants receiving alcohol in a 
similar study (Ramchandani et al. 2011).  However, the genotype effect on the response 
may be opposite from the effect of genotype on the alcohol response.  We also 
hypothesize that the PET studies with [11C]raclopride will show that 118GX subjects 
have less dopamine release during morphine administration than 118 AA subjects. 
 
 


 
 
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Table of Contents  
1. Introduction/ Scientific Rationale ................................................................................... 5 
2. Study objectives or hypotheses ....................................................................................... 8 
3. Subjects ........................................................................................................................... 9 
4. Study Design and Methods ........................................................................................... 11 
5. Storage of data and samples:......................................................................................... 19 
6. Additional Considerations ............................................................................................ 20 
7. Risks/ discomforts ......................................................................................................... 20 
8. Subject monitoring ........................................................................................................ 23 
9. Outcome measures ........................................................................................................ 23 
10. Statistical Analysis ...................................................................................................... 24 
11. Human Subjects Protection ......................................................................................... 25 
12. Anticipated Benefit ..................................................................................................... 28 
13. Summary/ classification of risk: ................................................................................. 28 
14. Consent documents and process ................................................................................. 29 
15. Data and Safety monitoring ........................................................................................ 29 
16. Quality Assurance ....................................................................................................... 30 
17. Adverse event reporting .............................................................................................. 31 
18. Alternatives to participation or alternative therapies .................................................. 31 
19. Confidentiality ............................................................................................................ 31 
20. Conflict of Interest ...................................................................................................... 31 
21. Technology Transfer ................................................................................................... 32 
22. Research and Travel Compensation............................................................................ 32 
23. References ................................................................................................................... 33 
Appendix I - Questionnaires ............................................................................................. 38 
Appendix II. Recruiting advertisements ........................................................................... 49 
Appendix III. Screening questionnaires for Patient Recruitment Office .......................... 50 
Appendix IV. Investigator’s Brochure .............................................................................. 53 
Appendix VI. Other – Evaluation to sign consent and expected answers ........................ 54 
Appendix VII. Results from mouse study......................................................................... 56 
Appendix IX.  1SE Inpatient Nursing Information Sheet ................................................. 57 
Appendix X. Plan for clinical monitoring of participants receiving morphine at NIDA . 59 
Appendix XI. Plan for clinical monitoring of participants receiving morphine at the NIH 
Clinical Center in the Course of PET sessions ................................................................. 61 
 
List of Abbreviations  
ACTH - Adrenocorticotropic hormone 
aCPRS – abbreviated Comprehensive Psychopathology Rating Scales 
BPI - Brief Pain Inventory 
DA – dopamine 
DEQ – Drug Effects Questionnaire 
DTI – Diffusion Tensor Imaging 
OPRM1 – gene for µ opiate receptor subtype 1  
PSQI - Pittsburgh Sleep Quality Index  
ROI – Region of Interest 
VAS - visual analog scale 


 
 
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1. Introduction/ Scientific Rationale 
Background 
Dependence on oral prescription analgesics has become an increasing problem for young 
people in the US.  Among adolescents, prescription and over-the-counter medications 
account for most of the commonly abused illicit drugs by high school seniors 
(http://www.drugabuse.gov/publications/topics-in-brief/prescription-drug-abuse).  
Prescription opioids interact with µ-opioid receptors. All opioids can be highly addictive 
and altering the route of administration (e.g., snorting or injecting) can intensify the 
effect.  Furthermore some abusers of prescription opioids report moving from 
prescription opioids to heroin or resorting to using heroin when they cannot get the pills.  
Of all abused substances, opioid abuse has the highest death rate among users (Callaghan 
et al. 2012).  Abuse or dependence on prescription opioids is estimated to occur in about 
1.9 million people in the U.S.  Furthermore, men were more likely than women to 
endorse addictive behaviors related to prescription opioids (early prescription refills, 
physician refusal to prescribe because of abuse concerns; odds ratio 1.95; (Glass et al. 
1993)).  
The heritability for opioid dependence has been estimated to be about 50% (Tsuang et al. 
1996;Tsuang et al. 1998).  Genetic variation at the µ-opioid (OPRM-1) gene locus is an 
important candidate factor for susceptibility to alcoholism, differential alcohol responses, 
and differential treatment responses to pharmacological treatments and is also thought to 
be a factor in opiate abuse. The endogenous opioid system is central to the function and 
modulation of mesolimbic dopaminergic signaling, a physiological system likely 
involved in the reinforcing properties of all drugs of abuse with the exception of sedative-
hypnotics (Kreek et al. 2002;Contet et al. 2004).  Quantitative trait locus studies and 
experiments with OPRM1 knockout mice have demonstrated the critical role played by 
this receptor in both opiate and alcohol self-administration (Becker et al. 2000;Belknap 
and Crabbe 1992;LaForge et al. 2000;Matthes et al. 1996;Roberts et al. 2000).  
A common functional A118G single-nucleotide polymorphism (SNP) has been identified 
in the coding region of exon 1 of the OPRM1 gene which has a high-enough frequency 
(10.5% in a New York City population (Bond et al. 1998), 26% in a European population 
(Bart et al. 2004), 24% in a European-American population (Zhang et al. 2006), 40% in a 
study of a Chinese population (Zhang et al. 2007), and up to 60% in some Asian 
populations (Tan et al. 2003)) to make it a practical candidate for prospective research.  
In one study the A/G genotype was present in significantly more heroin users than in 
controls (25.6% vs. 3.8%)(Drakenberg et al. 2006), but another study did not find a 
greater incidence of the A/G genotype in either heroin or alcohol abusers (Franke et al. 
2001).   
Human association studies have been inconsistent in demonstrating a relationship 
between and heroin addiction and the A118G SNP.  Szeto et al. (2001) found a 
significant association with the 118G variant among 200 heroin addicts in Hong Kong 
compared to 97 healthy controls.  The G allele was present in 39.5% of the addict 
population, vs. 29.4% of controls, with 16.5% of the addicts being GG homozygotes vs. 
11.3% in controls (p=0.02).  Tan et al. (2003) found highly significant differences 
between ethnic groups among four different Asian populations in allele and genotype 
frequencies; however, the only significant association between heroin dependence and 


 
 
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genotype distribution (p=0.024) and allele frequency (p=0.009) was in Indians.  Bart et 
al. (2004) as well as Drakenberg et al. (2006) found and association between G-allele 
carrier status and heroin dependence, but another study did not find a greater frequency 
of the G allele in either heroin or alcohol abusers (Franke et al. 2001). Inconsistent 
findings in association studies are common in psychiatric genetics, in part due to limited 
power of highly heterogeneous categorical disease phenotypes. Experimentally based 
intermediate phenotype approaches are therefore an important complement to association 
studies.   
In that context, a [11C]raclopride PET study showed a robust release of dopamine 
following an alcohol challenge compared to placebo in social drinkers who carried the G 
allele (Ramchandani et al. 2011).  The effect of the G allele on µ opioid receptor binding 
with PET and [11C]carfentanil has been studied in alcohol-dependent participants and in 
smokers (Weerts et al. 2012;Ray et al. 2011).  There was no effect of alcohol dependence 
on the binding of [11C]carfentanil, but carriers of the G allele had lower global binding 
potential (BPND) for the radioligand (Weerts et al. 2012).  A similar lower binding 
potential was observed in smokers carrying the G allele, and the lower binding potential 
in some of the regions assayed was associated with greater subjective reward from 
smoking (Ray et al. 2011).   
The effect of the G allele on pain perception has been studied in various conditions.  
Fillingim et al. (2005) demonstrated a significant difference in pressure pain threshold in 
individuals with the 118G variant SNP. Interestingly, this threshold difference was higher 
among men and lower among women with the 118G SNP as compared to controls.  
Nonetheless, the effect of fentanyl on perceived labor pain was greater in women 
carrying the G allele than in women homozygous for A resulting in the need for less 
analgesic (Landau et al. 2008).  However the effect was opposite in a study by Oertel et 
al. (2008). 
Bond et al. (1998) using Xenopus oocyte cells, found that receptors encoded by the 
variant 118G allele showed increased affinity for the endogenous -opioid ligand -
endorphin in vitro, leading to increased activation of G-protein activated inwardly 
rectifying potassium channels following binding of -endorphin (Bond et al. 1998).  
However, Befort et al.(2001) found no difference in binding affinity of -endorphin 
between wild type and A118G-coded -opioid receptors using an in vitro model with 
COS cells.  Similarly, Beyer et al.(2001) found no difference in -opioid binding 
between wild type and A118G coded receptors using an in vitro HEK 293 cell model.  
These discrepant in vitro results reinforce the importance of examining the functional role 
of the -opioid receptor in the correct context, both at the cellular level, where coupling, 
etc. may be determined by cell type, and at the level of the integrated organism.  
Using mouse lines that were modified to express either the human A allele or G allele for 
the OPRM1, Ramchandani et al. (2011), found a 4-fold greater dopamine release from an 
ethanol infusions in the mice carrying the G allele.  However, in vitro autoradiography of 
the -opioid receptor with [3H]DAMGO showed no difference between mouse lines.  
Current studies in collaboration with Drs. Shippenberg and Chefer at the NIDA IRP are 
testing dopamine release by microdialysis and with Mr. J. Elliot Robinson at the 
University of North Carolina are testing the effects on intracranial self stimulation (ICSS) 


 
 
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in these mouse lines in response to various opioid agonists.  The results of these studies 
showed that morphine, but not fentanyl, oxycodone or buprenorphine reduced the 
threshold for ICSS in the mice homozygous for the A allele, but not in those mice 
homozygous for the G allele.  The microdialysis studies with morphine were consistent 
with the effects on ICSS; morphine induced release of dopamine was lower in the G/G 
mice than in the A/A mice. These results suggest that the discrepant results observed in 
genetically engineered cells designed to evaluate the effect of the 118G allele on -
endorphin binding and G-protein mediated intracellular effects (Bond et al. 1998;Beyer et 
al. 2004) may have been a result of using cells artificially modified to express the 
A118G-coded receptor and thus may be an artifact of the cell line or genetic engineering 
model selected. 
The mixed results in human population studies of the relationship between the A118G 
polymorphism and substance dependence may be confounded by two important issues.  
First is the inherent difficulty of isolating a small factor such as SNP genotype in a large 
and diverse population.  Second, the role played by the A118G SNP in heroin 
dependence (if any exists) may be more evident in the initiation or development of the 
drug-taking behavior in younger or more naïve populations than its maintenance in 
mature or dependent populations.  A previous [11C]raclopride PET study showed a robust 
release of dopamine following an alcohol challenge compared to placebo in social 
drinkers who carried the G allele (Ramchandani et al. 2011).  PET studies of dopamine 
release after an opioid challenge have been inconsistent (Spreckelmeyer et al. 
2011;Hagelberg et al. 2002;Daglish et al. 2008).  The reasons for these inconsistencies 
are unknown, but may be due to the genetic makeup of the participants, which was not 
tested or to the opioid used as the challenge.  In the study by Spreckelmeyer et al. (2011), 
remifentanil (0.3 g/kg) was used and the authors suggest that this drug is most similar to 
the endogenous opioid, -endorphin.  No human studies to date have tested the effect of 
morphine on dopamine release, but it is expected to cause dopamine release as observed 
with microdialysis in rodents. 
As the study outlined in the present protocol aims to examine whether OPRM1 A118G 
variation moderates the mesolimbic DA response to µ-opioid receptor activation, it is 
important that we have a signal that could be modified. Using non-human primates, it 
was previously found that the rhesus ortholog of the human OPRM1 A118G SNP only 
moderated alcohol-induced psychomotor stimulation (a marker of mesolimbic DA 
activation) in males but not in females (Barr et al. 2007). This difference was presumably 
due to the negligible overall psychomotor response in the latter group. In agreement with 
those observations, a subsequent human PET study (Urban et al. 2010;Barr et al. 2007) 
found only marginal alcohol-induced DA release (measured as % change in 
[11C]raclopride binding potential) in females, while a robust response was present in 
males. Alcohol activates mesolimbic DA neurons indirectly, through release of 
endogenous opioids and their actions at µ-opioid receptors (Heilig et al. 2011;Urban et al. 
2010). Because endogenous opioid release in response to alcohol does not differ between 
men and women (Mitchell et al. 2012), it must be concluded that the observed sex 
differences are likely to be postsynaptic. A similar sexual dimorphism is therefore likely 
to exist for actions of an exogenous µ-agonist. Taken together, these observations thus 


 
 
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make it unlikely that the hypothesis of the present study can be addressed in females, 
providing a compelling scientific rationale for restricting recruitment to males. 
We will therefore examine the role of the A118G SNP for subjective and objective 
responses to a standardized intravenous morphine challenge in opioid experienced, non-
dependent males.  Subjective psychological and objective psycho-physiological 
responses, as well as brain dopamine release will be examined in response to the 
challenge, all using well-established methods as described below. To effectively 
investigate a relationship between this polymorphism (A118G) and the endophenotype in 
question (persons likely to abuse/become dependent on opiates), we plan to identify an 
adequate sample of subjects with and without the genotype in question, but without 
opiate dependence, and compare their responses to an opiate under controlled conditions.  
As the frequency of the G allele varies among ethnic populations, we will obtain self-
reports of race and ethnicity and obtain ancestry scores from large SNP panels to control 
for potential differences between carriers of the G allele and A allele homozygotes. 
The following tests are known to be sensitive to opioid effects and will be used in this 
study: 
1. 
McGill Pain – Cold Pressor Test  (Posner et al. 1985) 
2. 
Pupillary constriction 
3. 
Drug Effect Questionnaire (DEQ) (Holdstock and de Wit 1999) 
4. 
Respiratory Rate 
5. 
Pulse Oximetry (a measure of oxygen saturation in blood). 
  
Name and description of treatment(s):  [11C] raclopride will be administered under an 
IND held by the Clinical Center PET Department.  
Morphine (10 mg/70 kg) will be administered as a sterile solution of 2 mg/ml over 1 
minute.   
Subjects will also receive an MRI (about 5 minutes) for co-registration with the PET.  In 
addition, a resting scan (approximately 5 minutes) to assess connectivity of brain regions 
at rest and a diffusion tensor imaging (DTI) scan (about 7 minutes) to assess white matter 
integrity will be acquired.  The purpose of these MRI scans is to determine if there is an 
effect of the OPRM1 genotype on brain connectivity (resting state), and its relationship to 
genetic-induced alterations in dopamine release. In addition, the structural MRI is 
required for the PET scan (and functional scan) alignments. These tests will be done only 
once and not performed while the participant is receiving the opiate challenge.  The DTI 
scans are being performed to examine the relationship of white matter integrity to the 
above dependent variables. 
Statement of GCP: The study will be carried out following standard guidelines for good 
clinical practice.  
2. Study objectives or hypotheses 
a. Hypotheses: 
Homozygous carriers of the 118A allele of the -opioid receptor will show greater 
positive subjective response to the morphine than those carrying one or two copies of the 


 
 
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118G allele (118GX), paralleled by lower binding potential for [11C] raclopride following 
morphine injection because of greater dopamine release than carriers of the G allele.   
Objectives: 
a.Primary objectives: To examine the role of the -opioid receptor 
polymorphism OPRM1 A118G on the subjective and objective effects, 
including dopamine release, of the -opioid agonist morphine. 
b.Secondary objectives: A number of exploratory analyses will be carried 
out with the collected data to generate hypotheses on the relation of patient 
characteristics (e.g. family history of alcohol/drug use disorders, pain, mood, 
etc.), physiological opiate responses (e.g., pupil constriction, cardiovascular 
parameters such as respiratory rate and % oxygen saturation as measured by 
Pulse Ox), endocrine responses (cortisol, ACTH), pain threshold (measured 
by cold pressor test), MRI scans, and positive psychological effects (as 
measured via visual analog scale) with DA release measured by PET. 
3. Subjects 
a. Description of study populations  
i. Brief description of subject groups 
Subjects will be 21-55 year-old, non-nicotine dependent male volunteers who have taken 
prescription pain pills without negative effects in the past, but are not currently taking 
them or dependent on them. All participants will be in good health, non-smokers or light 
smokers (< 20 cigarettes/week), current non drinkers or social drinkers; participants 
should not meet DSM IV criteria for alcohol abuse or alcohol dependence.  Subjects will 
be recruited into two groups: 1) subjects homozygous for the major 118A allele (118AA 
genotype) of the OPRM1 polymorphism; 2) subjects carrying one or two copies of the 
variant 118G allele (118AG or 118GG genotype, hereafter called 118GX) of the OPRM1 
polymorphism.  
The requirement that there is experience with prescription pain pills is in place because 
we do not wish to administer an opiate to naïve volunteers. Prior experience with opioid 
pain medications enhances safety and aids in the exclusion of potential participants who 
have had negative experiences (e.g., allergic response, excessive nausea and/or vomiting, 
itching) as these side effects could make obtaining the PET scan difficult.  The 
experience of an individual who has taken even one or two prescription pain pills should 
provide enough information regarding negative side effects to eliminate people with 
allergies or negative experiences.  In addition, participants will be excluded if they have 
used pills chronically (> 6 weeks) or recently (within the previous 3 months).  The 
purpose of these criteria is to remove possible residual effects on the receptor.   
We have chosen to restrict the study population to ages 21-55 years to reduce age-related 
variability in the study. Since the ventral striatum shrinks an average of 3.6 to 3.7% per 
decade (Gunning-Dixon et al. 1998), a wider age range introduces significant and 
avoidable variance in the study group.   
We have chosen to restrict the study to men only based on the lack of an effect in women 
on DA release during the administration of alcohol as the effect of alcohol on DA release 


 
 
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is presumed to occur through the µ-opioid receptor (Barr et al. 2007;Mitchell et al. 
2012;Urban et al. 2010).   
ii. Target number of completers: 80 completers 
iii. Withdrawals or dropouts will be replaced 
b. 
Inclusion criteria 
1. Male participants between 21-55 years of age. 
2. Good health as determined by medical history, physical exam, EKG and lab tests. 
3. Current non-smokers or light smokers or e-cigarette users (<20 cig/week) who 
can easily abstain from smoking or using e-cigarettes for 1-2 days/week. 
4. Current non-drinkers or social drinkers who do not meet past or current DSM IV 
criteria for alcohol abuse or alcohol dependence. 
5. An equal number of final participants will be of OPRM1 118 A/A vs. 118A/G or 
118G/G genotype. This means that after the first group (n40) is complete then 
only participants with the required genotype for the other group will be included. 
6. Prior opiate use, at least one experience with one of the opiates in the list in 
Appendix 1 (p. 34).  
7. Comprehension/fluency with English Language. 
 
c. 
Exclusion criteria 
1. Current or prior history of any significant disease, including cardiovascular, 
respiratory, gastrointestinal, hepatic, renal, endocrine, or reproductive disorders, 
or a positive hepatitis or HIV test at screening, disorders that could make 
administration of an opiate more risky (e.g., asthma, COPD, sleep apnea, or other 
breathing disorders; liver or kidney disease; thyroid disorder; trouble swallowing, 
or a blockage in the digestive tract (stomach or intestines); neurologic disorders 
(e.g., a history of head injury or brain tumor, epilepsy or other seizure disorder, 
CVA, migraine in treatment, etc.); low blood pressure; hypertension; 
neuromuscular disorder; gallbladder disease; Addison's disease or other adrenal 
gland disorders; enlarged prostate, urination problems)  
2. Current Axis-I psychiatric illness as determined by the Structured Clinical 
Interview for DSM IV disorders (SCID). 
3. Current or prior history of any alcohol or drug dependence as determined by the 
Structured Clinical Interview for DSM IV disorders (SCID). 
4. Positive result on urine screen for illicit drugs. 
5. Medication use: 
a) Current chronic prescription or over the counter medications or use of 
prescription or OTC medications known to interact with dopamine receptors 
within 2 weeks of the study.   
b) Drugs known to inhibit or induce enzymes that metabolize opiates should not 
be used for 4 weeks prior to the study.  These include chlorzoxazone, 
isoniazid, metronidazole and disulfiram.   
c) Cough-and-cold preparations that contain anti-histamines or opiate pain 
medicines will be withheld for at least 72 hours prior to each study session. 


 
 
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d) Drugs that may interfere with the BOLD MRI signal within 2 weeks of the 
study.  These include, but may not be limited to: muscle relaxants or 
respiratory, cardiovascular or anticonvulsant medications. 
6. Morbid obesity (BMI >40 kg/m2) 
7. Previous negative effects of opioid administration 
8. Presence of certain implanted devices (cardiac pacemaker or neurostimulator, 
some artificial joints, metal pins, surgical clips or other implanted metal parts), 
body morphology, or claustrophobia. Justification: Implanted devices may 
increase the risk of MRI scanning and/or adversely affect the quality of the data; 
body morphology may prevent optimal positioning in the scanner and thus affect 
the quality of the data; participants with claustrophobia may find the MRI scan 
too unpleasant and may exhibit excess movement that will adversely affect the 
quality of the data. Assessment tool(s): Prospective participants will fill out an 
MRI screening questionnaire and undergo an interview with an MR technologist.  
Questions concerning suitability for scanning will be referred to the Medical 
Advisory Investigator.  Prospective participants will be questioned about 
symptoms of claustrophobia and placed in the mock scanner during their first visit 
to assess for possible difficulty tolerating the confinement of the scanner and for 
ability to fit into the scanner. 
9. Conditions restricting participant’s ability to lie flat for up to two hours (such as 
coagulopathies, superficial or deep vein thrombosis, or musculoskeletal 
abnormalities).  Justification: PET scanning sessions require participants to lie 
flat on their backs and remain perfectly still for approximately two hours. 
Therefore, conditions that would make that difficult (e.g. chronic back pain, 
significant scoliosis) or dangerous (e.g. familial hypercoagulability syndrome, 
history of thrombosis) will be exclusionary. Assessment tool(s): History and 
physical examination by a qualified IRP clinician, supplemented with a trial of 
lying in the mock scanner to assess comfort. 
10. Head trauma leading to loss of consciousness for more than 5 min or 
hospitalization 
11. Exposure to ionizing radiation from research studies that, in combination with the 
study tracer, would result in cumulative exposure of >5 rem within the previous 
12 month period. 
12. Self-reported and/or observed signs, symptoms, or diagnosis of Raynaud’s or 
Buerger’s disease (e.g., pain in hands or feet at times of rest, during/following 
cold exposure or stress, any significant color changes in hands or toes).  
Additionally, medical staff will be present to watch for these symptoms during the 
actual cold pressor test. 
 
4. Study Design and Methods 
a. Study overview – 
The study will require at least 4 visits by the participants.  Each visit will last 
approximately 5-8 hours.  Visits 1 (consent visit) and 2 (toleration visit) will be at the 
BRC in Baltimore, the other two visits (Visits 3 and 4) will be conducted in the NIAAA 
Outpatient clinic and the PET scanning facility of the Clinical Center in Bethesda.  The 


 
 
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first two visits will be outpatient visits.  Participation in 10-DA-N457 will be encouraged, 
but not required.  Protocol 10-DA-N457 provides for more generalized genetic testing in 
conjunction with other neuropsychological tasks. Each participant will be scheduled for 
structural, resting state and diffusion tensor imaging MRI scans on one of the study days 
or on a separate day if that is not possible in Baltimore.  The participants will spend the 
night before each of the PET studies in the NIAAA inpatient ward (1SE Unit) at the NIH 
Clinical Center. 
During the screening visit performed under the screening protocol (06-DA-N415), MMG 
will screen healthy participants from a population who have had experience with oral 
prescription analgesics to obtain samples of two groups of subjects: 1) subjects 
homozygous for the major 118A allele (118AA genotype) of the OPRM1 polymorphism; 
2) subjects carrying one or two copies of the variant 118G allele (118AG or 118GG 
genotype, hereafter called 118GX) of the OPRM1 polymorphism.  At the time of consent 
to 13-AA-0061 the entire study will be explained and the participant given the 
opportunity to enroll in the study.  During the consent visit (hereafter called Visit 1 of the 
protocol) or the next visit, participants will be given a questionnaire to evaluate his 
previous response to oral prescription analgesics (See Appendix I).  During Visit 1 or 
another visit, the participant will undergo the MRI portion of the study. 
During Visit 2, participants, who successfully pass the initial screening and enroll in the 
study after the consent interview, will receive a placebo injection and subsequently a 
standardized opiate challenge. The opiate challenge will be a standardized IV injection of 
morphine, (10.0 mg/70 kg; 2 mg/ml) administered over 1 minute.   
Post-placebo) and post-morphine injection measures will be made in two areas: 1) 
subjective response as measured by a standardized questionnaire (DEQ), and 2) objective 
measures response. We will determine their response to a cold pressor pain test, and a 
measurement of their pupillary constriction as well as several other tests of their response 
to the morphine, including continuous Pulse Ox monitoring and intermittent monitoring 
of their respiratory rate, heart rate, EKG and blood pressure. Blood will be collected to 
measure plasma ACTH and cortisol levels as they may be suppressed by activation of the 
−opioid receptor. Retrospectively, participants will be asked to evaluate their peak 
experience to the morphine on a Likert-like visual analog scale (VAS), which will 
include sedation, euphoria, dizziness, fatigue, depression, tremors, anxiousness, upset 
stomach/nausea, dry mouth, and headache, which are common side effects of opiate 
administration (Appendix I).  We hypothesize that 118AA subjects will have significantly 
higher subjective response to the morphine challenge than 118GX subjects.  
On two more separate visits, at least a week apart (Visits 3 and 4), participants will report 
to the Clinical Center in Bethesda for an overnight stay before each PET scan.  We will 
repeat the injection procedure in all participants twice in the PET scanner, once injecting 
morphine and once injecting saline, and assess the binding potential of [11C]raclopride, a 
positron emitter labeled ligand which binds preferentially to D2 dopamine receptors.  The 
difference between the binding potential following the saline injection and that during the 
morphine injection will provide a measure of dopamine release.  We hypothesize that 
118AA subjects will have a lower binding potential with [11C]raclopride from the 
morphine injection relative to placebo, indicating greater amounts of dopamine release 
than those subjects carrying one or two copies of the G allele.  


 
 
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b. 
Recruitment 
This study employs an experiment of nature, i.e. genetic variability, as a basis for group 
assignment. To obtain the respective groups, this protocol will be conducted in the 
following phases:   
1. Recruitment of potential participants through approved advertising media (see 
draft ad in Appendix II). 
2. Thorough screening of selected participants according to 06-DA-N415 
(“Screening Protocol for the Evaluation of Potential Research Subjects”). 
3. Genotyping, which will allocate subjects into two groups: A) 118AA 
homozygotes, and B) 118AG heterozygotes, and 118GG homozygotes 
4. An invitation to members of each group to join the study with an effort to balance 
the groups demographically, most likely by trying to match group B. 
Ads will be placed in approved media seeking healthy volunteers between ages 21-55 
years. The ads will specify that volunteers must have had experience with prescription 
analgesics (e.g., Oxycontin, Vicodin, oxycodone), but are no longer needing these 
medications. They must be willing to undergo genotyping to determine whether they are 
homozygous, heterozygous, or negative for the 118G SNP (as per methodology of Skarke 
et al. (2004)). 
c. 
Screening  
An initial screen will be accomplished by phone using the standard MMG phone screen.  
If the participants appear to qualify based on the inclusion and exclusion criteria, they 
will be invited for an in-person screening visit, consisting of informed consent 
procedures, blood draws for genotyping and basic medical evaluation for 
inclusion/exclusion criteria.  The screening evaluation will include: 
1. medical history 
2. drinking and drug use history using the Drug Use Survey  
3. Structured Clinical Interview for DSM-IV (SCID) psychiatric diagnoses including 
alcohol or drug dependence as currently administered by MMG. 
4. physical examination, including EKG 
5. fasting blood samples for routine blood chemistry, complete blood count (CBC), 
liver function, hepatitis B and hepatitis C, a serum HIV screen, and TSH  
6. urine sample for illicit drug screen 
7. MRI screen. 
8. The determination of a lack of nicotine dependence will be based on the potential 
participant’s stated ability to regularly abstain from smoking for 1-2 days/week.  
9. Tuberculin skin testing  
The study will be open to participants of all races. All participants will be recruited 
through approved advertising media. Participants go through a consent interview during 
which the study will be fully explained.  If they chose to enroll, they will sign the 
informed consent form prior to enrollment in the study.  
d. 
Study Procedures 
Study Overview: 


 
 
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Visit 1 – This visit will involve reviewing the consent and if the person agrees to 
participate, may involve additional questionnaires and the MRI scans.  It may be 
necessary to schedule these procedures on a separate day. 
Visits 2-4 -Subjects will receive four injections on three separate days, two morphine 
injections and two placebo injections.  During Visit 2, the first injection will be placebo 
(normal saline) and the second will be morphine to measure its subjective and 
physiological effects prior to the PET sessions; the other two injections, morphine or 
placebo, will be given while the participant is undergoing a PET scans with 
[11C]raclopride (Visits 3 and 4). The injections during Visit 2 will be conducted at the 
BRC. The injections during Visits 3 and 4 will be conducted during PET in the Nuclear 
Medicine department at the NIH Clinical Center. 
During the study visits that do not involve the PET scans, participants will arrive at the 
BRC by 8:00AM on the morning of testing, following an overnight fast, and after 
abstaining from alcohol and all medications for 72 hours. To minimize variance in 
caffeine consumption, patients will be asked to report to the clinic having had no 
caffeinated coffee, tea, or soda in the morning.  
On days when participants could receive morphine (Visits 2, 3 or 4), they will be brought 
to the BRC or Clinical Center in a taxi paid for by NIH. Participants will receive a light 
breakfast (~300 cal). A breathalyzer test will be performed to ensure a zero breath alcohol 
concentration and a CO test for recent smoking or exposure to second hand smoke (a CO 
over 15 ppm indicates likely recent smoking and participant will be disqualified).  For 
subjects reporting use of e-cigarettes, recent use will be assessed by performing a cotinine 
salivary test such as NicAlert (a cotinine value over 1 indicates likely recent e-cigarette 
use and participant will be disqualified). 
During Visit 1 after giving informed consent or in a subsequent separate visit (herein 
termed Visit 1a), participants will complete assessments of baseline pain, sleep, and 
depression/anxiety as these may impact subjective assessment of drug effects - Brief Pain 
Inventory (BPI), abbreviated Comprehensive Psychopathology Rating Scales (aCPRS), 
WHO QOL Bref, Sleep Disorders Questionnaire, and Pittsburgh Sleep Quality Index 
(PSQI).  The MRI scans, which will be completed before Visits 3 and 4, may occur 
during Visit 1 or 1a. 
During Visit 2, physiological responses (RR, HR, EKG and oxygen saturation) will be 
monitored using standard instrumentation (EKG, pulse oximetry) continuously for 60 
min after injections or until they return to normal and values for these parameters as well 
as for BP will be recorded approximately every 5 min for the duration of the drug effect.  
In addition, physiological responses will be collected continuously on the AutoSense, a 
wearable suite of sensors for physiological monitoring in the daily environment.  
AutoSense was developed by a group of computer scientists at the University of 
Memphis, led by Dr. Santosh Kumar.  Parameters measured by AutoSense include 
respiration rate, heart rate, heart-rate variability, skin conductance, and activity level.  
The sensors are hosted on a tiny computing platform called a wireless sensor mote (with 
dimensions similar to those of the memory cards used in digital cameras).  Sensors are 
attached to an elastic belt that is worn around the chest.  Two electrodes, similar to those 
used in ECGs, are placed on the chest and connected to the sensors in the belt.  Data are 


 
 
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sent wirelessly to a pre-programmed smart phone for temporary storage. These data 
collected during administration of morphine under controlled laboratory conditions will 
be used to develop an algorithm to detect opioid administration in future field studies.   
MRI scans: 
All MRI scans will be performed in the Trio at the BRC. The participants will not receive 
any drug before these scans.  Under this protocol or 10-DA-N457, a structural MRI of the 
brain for co-registration with the PET scan as well as resting state and DTI MRI scans of 
the brain will typically be obtained on the day of Visit 1 or 1a at the BRC. As many 
participants enroll in multiple studies, the participant may have already enrolled in 10-
DA-N457 and the scans acquired under that protocol may have already been performed 
and will be used for this protocol.   
Repeating the MRI scans - Because excessive head movement is an obstacle to obtaining 
quality fMRI data, participants who generate unusable data (or if there is an equipment 
failure) during their scanning session may be asked to repeat the session.  Repeating the 
session will maximize the risk/benefit ratio of the MRI scanning as it will allow 
completion of all aspects of the study.   
Participants will be given a meal once collection of dependent measures is complete.  
After the meal, orthostatic vitals will be obtained and if there is no evidence of 
symptomatic orthostasis the participant will be discharged.  
Visit 2  Morphine injection with subjective and physiological measures (Toleration 
Study): 
The purpose of this visit is two-fold.  The first is to reduce the likelihood that side effects 
like vomiting will occur in the PET scanner.  The second is to obtain data on the 
participant’s responses (pain response and pupil response) to morphine at a time when the 
participant is not in the scanner when such measurements would be more difficult to 
acquire.  Following a prestudy nursing assessment, which includes urine toxicology, 
breathalyzer, CO monitoring, HR, BP, RR, and weight, two indwelling intravenous 
catheters will be inserted, one each into the antecubital vein of the arm using sterile 
technique. The following table summarizes the prestudy nursing assessments obtained: 
 
Measurement 
Parameter(s) to proceed 
Breathalyzer 
Negative 
CO test 
≤ 15 ppm 
Urine toxicology 
Negative 
Heart rate* 
≥50 bpm and ≤105 bpm 
Systolic blood pressure* 
≥95 mmHg and ≤135 mmHg 
Diastolic blood pressure* 
≥60 mmHg and ≤90 mmHg 
Respiratory rate* 
≥8 and ≤24 breaths per minute 
Oxygen saturation* 
≥94% 
 
One catheter will be used for the placebo and morphine injections and the other will be 
used for blood sampling.  A nurse will monitor HR, BP, RR, ECG and blood oxygen 
saturation throughout the study.  Measurements will be recorded at 5 min intervals after 
either the placebo or morphine injection.  The measurements will be recorded for at least 


 
 
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60 min or until values have returned to the normal range.  A nurse will place the 
AutoSense ECG electrodes and respiration band on the participant’s chest for continuous 
physiological monitoring throughout the session.  Monitoring by the AutoSense will be in 
addition to monitoring by traditional methods. 
Baseline measurements (as described below) will then be obtained. After this, the placebo 
injection (normal saline in a volume equal to that used for the morphine injection) will be 
given (at approximately 9:45AM).  
At baseline as well as during and after the injection, the following measures will be 
obtained, following the schedule outlined in the study-session flow-sheet (Table 1): 
Subjective questionnaires: a visual analog scale of high and intoxication See Appendix I. 
for Drug Effects Questionnaire (DEQ) (Holdstock and de Wit 1999).  The DEQ consists 
of four visual analog scales used to describe current drug effects (feel drug effects, none 
(0) to a lot (l00)]; like the effects they feel, dislike (0) to neutral (50) to like extremely 
(l00); feel high, not at all (0) to a lot (l00); and (4) would like more not at all (0) to a lot 
(100).   
Objective Measurements: 1) Pupil constriction(Grace et al. 2010), cold pressor test 
(Posner 1991), and 2) Blood will be drawn at baseline and at 10 min after the injection 
for analysis of blood chemistries potentially responsive to an opiate challenge (including, 
but not limited to ACTH and cortisol) (Jaffe 1985).  
Cold Pressor Test: The cold water pressor test evaluates discomfort or pain when the 
nondominant hand is first placed in a warm water bath (37° C) for 2 min, then transferred 
to an ice water bath (0° C).  The participant is instructed to immerse his/her hand in the 
ice water for up to 3 min, but could withdraw the hand at any time if the pain becomes 
too great.  Participants are instructed to report verbally when they first sensed pain.  This 
time measures pain threshold.  Time to withdrawal measures pain endurance (Posner 
1991). See scoring sheet in Appendix I. 
Pupil constriction test: Participants will be instructed to sit quietly, blinking as little as 
possible while the pupillograph is positioned over the right eye by the operator.  While 
the participant focuses on a fixed point. The resting pupil diameter will be measured for 2 
s every 20 s for a total of one minute.  This test is a modification of a previously reported 
method (Grace et al. 2010) to remain within the time of the expected drug effect and will 
commence four minutes after the participant puts his hand in the cold water. 
The participant will be returned to the lounge for a relaxation period and a snack or 
lunch.  In early afternoon, the participant will return to the study room for the morphine 
injection, which will be administered by an NIH Credentialed physician with ACLS 
certification.  Participants will receive an injection of 10 mg/70 kg morphine (2 mg/ml) 
administered by an NIH Credentialed physician over 1 minute.  The tests described above 
will be repeated.  The participant will be monitored by an NIH Credentialed physician for 
the next 60 min or until HR, RR, BP, EKG and oxygen saturation have returned to 
normal ranges.  Values will be recorded approximately every 5 min (+/- 1) for the next 60 
min after the injection or until they have returned to normal ranges.   
 
 
 
 
 


 
 
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Table for Visit 2 
Minutes 
BL 0 5 10 15 20 25 30 35 40 45 50 55 
60 (plus additional 
records q. 10 min if not 
within normal range 
Morphine or 
placebo 
administration 
 
x  
 
 
 
 
 
 
 
 
 
 
 
HR, BP, RR, 
O2 Sat, EKG 
recorded * 
x 
 x x x x x x x x x x x 
x 
Cold Pressor 
Test 
 
 x 
 
 
 
 
 
 
 
 
 
 
 
DEQ 
x 
 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
Pupil 
constriction 
x 
 
 
x 
 
x 
 
x 
 
 
 
 
 
 
Blood draw for 
ACTH/cortisol*
* 
x 
 x 
 
 
 
x 
 
 
 
 
 
 
 
VAS 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
Please note the timing for these parameters will be as close as possible to the stated times, 
but may not be at exactly these times.  Data from cold pressor test, DEQ and pupilary 
constriction will be collected in sequence, not at the same time. 
*Please note monitoring of these parameters will be continuous until they have returned 
to normal ranges and recording of these parameters will continue at 10 min intervals if 
they have not returned to normal ranges.  It is expected that following the placebo 
injection, these values will be normal throughout the study, but they will be monitored for 
at least 60 min. 
 
** First blood draw for ACTH/cortisol will be after cold pressor test and DEQ, but before 
pupil constriction test.   
 
The AutoSense electrodes and respiration belt will be removed at the end of the session. 
Visits 3 and 4: PET studies of [11C]raclopride binding with and without morphine: 
Participant will be brought to the Clinical Center via taxi during the afternoon or early 
evening of each day before the scheduled PET studies. 
Outline of PET session procedures: 
1) Two IV lines will be started, one for injection of [11C]raclopride, the other for the 
morphine or placebo (normal saline in a volume equal to that used for the morphine 
injection) injection. 
2) Subjects will be placed in the PET scanner and administered a bolus of 
[11C]raclopride. 
3) Subjects will be administered either a morphine or a placebo (normal saline) injection 
using the procedure identical to that used in session 0. 
4) The subjective questionnaires will be administered at baseline and during the morphine 
or placebo (normal saline) challenge, identical to the procedures used in Visit 2.  Blood 
samples for blood chemistries will be drawn as described for Visit 2.  


 
 
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Detailed description of PET procedure: 
Scans will be performed with the GE Advance tomograph that acquires 35 simultaneous 
slices with 4.25 mm inter-slice distance.  Scans will be acquired in 3D mode with septa 
removed producing a reconstructed resolution of 6 mm in all directions.  The subject will 
be placed in the PET scanner, with the brain in the field of view. A thermoplastic mask 
will be made for each subject to gently immobilize the head while in the scanner. Each 
individual's mask will be used for each PET scan in that individual, to ensure similar 
head positioning.  First, a transmission scan lasting approximately 8-min will be acquired 
with two rotating rod sources for the purpose of attenuation correction.  The tracer will be 
prepared and tested for purity just prior to use.  
At 5 min following the morphine, which will be administered by an NIH Credentialed 
physician with ACLS certification, or placebo injection, up to 12 mCi [11C]raclopride 
will be administered as a bolus over one minute into the IV line in the opposite arm.  
Monitoring of HR, RR, BP, EKG and oxygen saturation will begin immediately by an 
NIH Credentialed physician.  Values will be recorded every 5 min for the duration of the 
PET scan by the nurse or nurse practitioner monitoring the study.  The participant will be 
asked how he feels in addition to the administration of the DEQ in the event he feels 
nauseous or needs to vomit.  He will also be encouraged to tell the study staff at any time 
if he feels nauseous or needs to vomit.  In the event that the participant experiences either 
of these side effects, he will be removed from the scanner until the effects subside or if 
they do not, the study will be discontinued.  As the participant cannot easily view the 
DEQ in paper form or on a computer while he is in the scanner, he will be asked to 
provide a number between 0 and 100 in response to the four DEQ questions. An NIH 
Credentialed physician with ACLS certification, will continue to monitor these values for 
60 min or until the values return to normal ranges.  Dynamic PET scans will begin with 
the [11C]raclopride injection and continue approximately 90 minutes to obtain optimal 
signal.   
The PET data from the placebo day will be used as a measure of baseline raclopride 
binding potential, using the Simplified Reference Tissue Model outlined by Lammertsma 
and Hume (1996). PET measurements taken following the morphine injection will be 
compared to that derived from placebo injection to measure the reduction in specific 
binding due to competition with dopamine endogenously released by the morphine 
challenge. The percent change from baseline has been shown to be proportional to the 
magnitude of dopamine release (Watabe et al. 2000).   
Table for Visits 3 and 4 
Minutes 
BL 0 5 10 15 20 25 30 35 40 45 50 55 60 70 80 90 95 
Morphine or placebo 
administration 
 
x  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
[11C]Raclopride 
injection, start scanning 
 
 x  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HR, BP, RR, O2 Sat, 
EKG recorded* 
x 
 x x x x x x x x x x 
x 
x x x x 
 
DEQ 
x 
 
 x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
 
 
 
End scanning 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
VAS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 


 
 
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Please note timing for these parameters will be as close as possible to the stated times, 
but may not be at exactly these times. 
 
*Please note monitoring of these parameters will be continuous throughout the scan and 
recording of these parameters will continue at 10 min intervals after the scan if they have 
not returned to normal ranges.  It is expected that during the visit in which the participant 
receives placebo, these values will be normal throughout the study, but they will be 
monitored for the same duration and at the same frequency as that for the morphine 
session. 
After the study is completed, subjects will return to the NIAAA inpatient area (1 SE) 
where they undergo a post scan assessment. If any medical complaints or concerns are 
voiced, appropriate medical attention will be provided. Subjects will be taken home by 
taxi paid for by NIH after receiving medical clearance from study investigator.  
End of Participation 
Participants will undergo a post-study assessment, typically on the last study session 
(Visit 4). The evaluation will include vital signs, EKG, CBC and blood chemistry. This 
evaluation will occur after the participant has been cleared for discharge. 
Visit 5 (by phone) The Lead Investigator or her designate will contact participants by 
phone the approximately one week after the study to ensure that there have been no 
unexpected adverse events. No other need for re-contact is anticipated. However, should 
the need arise for any reason, the names and contact information will remain on file with 
the NIH office of volunteer recruitment.  No information on the results of the genetics 
test or the results of the PET scans will be shared with the participants. 
5. Storage of data and samples: 
Plasma samples for cortisol and ACTH collected at the BRC will be stored temporarily in 
a freezer located in the Freezer room.  Plasma samples for cortisol and ACTH collected at 
the Clinical Center will be stored in a controlled access freezer room at the LCTS inside 
the NIH Clinical Center.  Samples collected at the BRC will be transferred to the Clinical 
Center by the NIDA courier at convenient intervals (once every month to two months 
depending on the number of participants).  The samples will be kept until they are 
analyzed, which is expected to be when all participants have completed the protocol.   All 
sample and data analyses are expected to be completed within 6 months of the last PET-
scan.  
Collection of blood for OPMR1 genotyping will be processed under the approved NIDA 
screening protocol (06-DA-N415).  Samples will be used to identify carriers of the G 
allele and those individuals who are homozygous for the A allele.  The DNA will also be 
collected during Visit 1.  It will be used to determine ancestry scores from large SNP 
panels.  Biological specimens obtained at the Clinical Center and those sent from the 
BRC will be stored in coded form (serial numeric codes) in freezers located in the access 
controlled Building 10 Hatfield CRC 1SE laboratory area of NIAAA/LCTS.  
Blood collected for genetic testing will be kept indefinitely for future analysis of relevant 
gene polymorphisms about which new data may emerge in the future literature. Blood 
obtained as part of this protocol will be stored in coded form (serial numeric codes) in a 


 
 
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freezer in the NIDA Freezer Room until they are shipped to NIAAA for analysis.  Once 
they are at NIAAA, they will be stored in freezers located in the access controlled 
Building 10 Hatfield CRC 1SE laboratory area of NIAAA/LCTS.  They will be analyzed 
for various biomarkers (at the NIAAA Lab of Clinical and Translational Studies).   
De-identified data from the AutoSense and age, gender, and drug use history will be sent 
to Dr. Kumar at the University of Memphis (Material Transfer Agreement #30749-10; 
expiration date 7/29/2016) and to Dr. Yixin Chen at Washington University (Data 
Transfer Agreement in process) for analysis. 
6. Additional Considerations 
a. Research with investigational drugs or devices  
i. Medications/devices requiring IND/IDE: 
The radiotracer, 11C raclopride, will be administered under IND 
#54135 held by NIH Clinical Center-PET Imaging Department 
The radiation exposure is for research purposes only. 
ii. Source of materials/storage/handling 
The radiotracers will be made by the radiochemists in the PET 
department. 
iii. Attach investigator’s brochure 
No investigator’s brochure is available. 
b. Gene Therapy 
i. Identify if gene therapy is used (if so, attach RAC documentation) 
No gene therapy will be done. 
7. Risks/ discomforts 
Known risks and discomforts associated with study procedures and medications: 
Morphine injection: 
Side effects from opiates can include sedation, euphoria, dizziness, fatigue, depression, 
tremors, sleeplessness, anxiousness, flu-like symptoms, upset stomach, vomiting, dry 
mouth, pupil constriction, itching, transient rash, hallucination, delirium, sweating, 
muscle and bone pain, confusion, extreme irritability, constipation and muscle spasms. 
Severe side effects can include severe respiratory depression, confusion or stupor, coma, 
clammy skin, circulatory collapse and cardiac arrest.  Sometimes, even in the case of 
individuals who later become addicted, initial injections may produce unpleasant 
sensations such as headache, dizziness, and nausea.  Participants will be encouraged to 
take extra fluids to avoid constipation. 
With the exception of allergic reactions, adverse effects of morphine are largely dose-
dependent, and the level of risk is therefore associated with the dose chosen. The FDA 
approved label recommends i.v. morphine doses between 4 – 10 mg/70 kg that can be 
repeated every 4 hours. In the present study, subjects will receive no more than a single 
morphine dose of 10 mg/70 kg on any given day. A literature search shows that when this 
dose was previously used in research volunteers, these experienced several central 
morphine effects, such as for instance feeling sleepy, clumsy, dizzy, high or intoxicated 
(Zacny et al. 1994a;Zacny et al. 1994b;Zacny et al. 1997a;Zacny et al. 1997b;Stoops et 


 
 
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al. 2012). It is therefore to be expected that some or all of these effects will be 
experienced by our participants. These effects are reversible, may cause discomfort, but 
do not pose a significant medical safety concern.  
The most important adverse effect of morphine, which does pose a significant medical 
risk, is that the drug can depress or stop breathing. Respiratory depression is dose 
dependent. Unless properly monitored and treated, it may lead to death. The five studies 
cited above together exposed 65 subjects to 10 mg morphine /70 kg (Zacny et al. 
1994a;Zacny et al. 1994b;Zacny et al. 1997a;Zacny et al. 1997b;Stoops et al. 2012).  One 
of the studies (Stoops et al. 2012) also included a 20 mg/70 kg dose, and demonstrated an 
orderly and linear dose-response relationship for end-tidal CO2, such that that 10 mg dose 
was intermediate between the 5 and 20 mg doses. The latter study also exposed subjects 
to multiple doses. No serious adverse events were observed after the 10 mg/70 kg 
morphine dose in any of the 65 published cases, and no serious adverse events were 
encountered in the paper using a 20 mg dose. In people receiving morphine after surgery, 
the incidence of respiratory depression has been estimated to less than one in a hundred 
subjects (Dahan et al. 2010). 
i. Steps taken to minimize risk 
Participants will be screened for a history of negative effects of opiate administration, and 
excluded if such a history is present. As all participants will have had experience with 
pain pills, it is expected that they will come to the study with knowledge of their previous 
experiences.  Participants will be excluded if they have used pills chronically (> 6 weeks) 
or recently (within the previous 3 months).  The purpose of these criteria is to remove the 
possibility of residual effects on the receptor. 
The potential adverse consequences of the morphine injection primarily involve 
respiratory depression, skeletal muscle rigidity, hypotension, bradycardia, nausea, 
dizziness or other impairment. Following the morphine injection, oxygen saturation, 
respiratory rate, blood pressure, and heart rate will be monitored continuously by an NIH 
Credentialed physician with ACLS certification for 60 min or until these values have 
returned to normal ranges.  Values will be recorded approximately every 5 min until they 
have returned to normal ranges.  Subjects who experience significant nausea, breathing 
difficulties, hypotension, or bradycardia will carefully monitored and supplemental 
oxygen, intravenous fluids, atropine, and naloxone will be available if needed.  Finally, 
risks of impairment are minimized by monitoring subjects until the effects of the opiate 
on motor performance or judgment have passed, and sending subjects home in a taxi.  
The study is designed to provide the first opiate challenge in the outpatient clinic, so that 
persons who react unfavorably to the challenge will be identified and excluded before 
becoming eligible for the PET scan procedure. Participants will be expected to be 
intoxicated at the conclusion of the opiate challenge. They will be supervised on site until 
any signs of drug effect have dissipated (e.g., vital signs in normal range and no signs of 
impairment) and the participant reports that they are not experiencing any drug effects at 
which time they should be able to safely to leave the NIH premises and will be taken 
home in a taxi arranged and paid for by the NIH. 
PET scan: 


 
 
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Potential risk of this procedure is primarily related to radiation exposure. The effective 
dose from the emission and transmission scans will be 0.62 rem, which is below RSC 
guidelines of 5.0 rem per year in adults. This risk has been assessed by separate Radiation 
Safety review, which assures that exposure is minimized, and falls within a widely 
accepted range. In summary, no harmful effect to humans has been observed from the 
levels of radiation used here. Additional measures taken to ensure subject safety will be 
to obtain a careful history of exposure to radiation from other sources or medical 
procedures to ensure that total exposure remains within an acceptable range.  
Some participants have reported a sense of claustrophobia or panic in reaction to 
placement in an MRI or PET scanner. Participants will be instructed to report such 
feelings so they can be removed from the apparatus and will not be required to continue 
with the session if they are uncomfortable with the procedure. If they cannot continue, 
this will require withdrawal from the study, and they will be paid for their participation 
up to that point. 
In summary, the risk / discomfort of the morphine injection procedure represents more 
than a minor increase over minimal, but is well justified by the scientific gains. 
MRI: 
MRI scans are routinely carried out both for clinical and research purposes. Individuals 
will complete an MRI safety checklist.  Subjects with metal objects in their body may be 
negatively affected, and are therefore excluded from this study. The enclosed space of the 
scanner can provoke anxiety in some individuals. If so, the scan is discontinued, where 
upon the anxiety resolves. Finally, MRI is a noisy process, so we require participants to 
wear foam earplugs while inside the scanner.  The risk / discomfort of this procedure is 
judged to be minimal.  
Genetic testing: 
No adverse events are anticipated as a result of the genotyping.  However, to protect 
confidentiality no genotyping data will be entered into the clinical record of participants 
in the study and no genotype data will be released to participants under any circumstance. 
No CLIA [Clinical Laboratory Improvement Act] certified genotyping acceptable for a 
clinical diagnostic or insurance purpose will be performed. In the study, there will be no 
identification of genetic diseases, and subsequently, and consequently, no relevant 
information to report to the participants.  The participants will be told that the medical 
relevance of the genotyping in this study is not established, while other information (e.g. 
a positive family history of drug problems) is a known indicator of susceptibility. 
Thus, this is considered a minimal risk / discomfort procedure. 
Pupillary constriction tests: 
This test is a widely used psychophysiological measure with minimal risk and 
discomfort. 
Cold pressor test: 
Participants may remove their hands when the pain becomes too much to continue.  
There is a 3 min cut-off, which eliminates any potential damage to the hand.  The 
participant is instructed to immerse his hand in the ice water for up to 3 min, but could 
withdraw the hand at any time if the pain becomes too great.  Participants are instructed 


 
 
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to report verbally when they first sensed pain.  This time measures pain threshold.  Time 
to withdrawal measures pain endurance. 
IV placement and Blood sampling: 
Minor discomfort is expected to result from blood draws and placement of IV lines. 
These procedures will be performed by qualified and credentialed NIH physicians, 
nurses, or technicians. Pressure will be applied to IV sites after lines are withdrawn to 
prevent subcutaneous bleeding. This follows standard clinical routine, and is considered 
to be a minimal risk/discomfort procedure.  Less than 450 ml of blood will be drawn as 
part of this research study. 
Autosense:  
Wearing the AutoSense belt may be inconvenient.  Participants may also experience 
slight discomfort and/or minor skin irritation while wearing the belt and electrodes.  
8. Subject monitoring 
Participants will be monitored by the medical, nursing and research staff for any 
untoward effect and the study session will be terminated for the participant if any major 
or unexpected adverse events occur. Oxygen saturation and heart rate will be monitored 
continuously throughout the study session.  Respiratory rate and blood pressure will be 
monitored every 5 minutes.  The MAI or another NIH Credentialed physician with ACLS 
certification will perform the morphine administration.   
Participants will assessed at the end of the day of Visits 2, 3 and 4 and will not be 
released until staff can document normal vital signs, an alert and oriented demeanor as 
well as a normal pupil response to light and have received clearance from attending study 
investigator (MD).  Any impairment in locomotor coordination or judgment will be 
monitored by the nursing and research staff.  The participant will be sent home in a cab 
paid for by the NIH.  
To evaluate for the possibility of adverse events, a safety assessment evaluation will be 
conducted at the completion of the last of the PET scan / injection study sessions.  This 
assessment will include vital sign determination, EKG, CBC, and blood chemistry. The 
Lead Investigator or her designate will contact the participant by phone, approximately 
one week after the completion of the study to evaluate for the possibility of any 
unexpected adverse events. 
Participants will be withdrawn from the study if they do not follow the instructions 
outlined in the protocol and informed consent form. Participants will also be withdrawn if 
they cannot tolerate the morphine injection and demonstrate any signs of untoward 
effects. Participants may also, at any time, choose to discontinue their participation in the 
study. 
9. Outcome measures 
a. The two primary outcome measures are: 
1) [11C]raclopride binding potential in striatal areas of the brain 
2) Subjective perceptions of morphine intoxication and opiate effects. 
b. Secondary measures are: 


 
 
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1) levels of neuroendocrine measures (ACTH, cortisol) 
2) pupillary constriction, respiratory rate, pain response 
10. Statistical Analysis 
 
a. 
Analysis of data/ study outcomes 
For the primary analyses, dependent variables (subjective and objective responses in the 
laboratory, post-morphine injection raclopride binding potential) will be analyzed using 
analysis of variance, with genotype as the independent factor. The role of drug and 
alcohol drinking history and family history of drug abuse/alcoholism as well as self-
reports of ancestry and genetically derived ancestry scores will be evaluated as covariates 
in the analysis. The level of significance will be set at 0.05. 
PET Analysis will be based on a Region of Interest (ROI) methodology. MRI scans will 
be performed on each participant, and co-registered with the participant’s PET scans. 
ROIs will be drawn in the nucleus accumbens, dorsal and ventral caudate and putamen, 
these being the main areas of post-synaptic dopamine release.  An ROI will also be 
placed on the cerebellum as this region is thought to be devoid of dopamine receptors and 
is used as the reference region because it provides a measure of nonspecific binding 
(Lammertsma and Hume 1996).  Dopamine release will be estimated by comparing 
[11C]raclopride binding potential derived using a bolus injection and the simplified 
reference tissue model (SRTM) under two different conditions (baseline vs. morphine) 
during separate scans conducted in randomized order. 
Baseline binding potential, changes in binding potential following morphine challenge, 
and subjective effects of the challenge as measured by changes in stimulation and 
intoxication scores on subjective perception scales between dose conditions (opiate vs. 
placebo) will be correlated.   
a. Power analysis  
Sample size: 
In a study that evaluated the effect of remifentanil administration on D2 dopamine 
receptor availability using a different PET radioligand in detoxified alcohol dependent 
participants (N=11) and controls (N=11) found a significantly reduced dopamine D2/3 
receptor availability after administration compared with baseline in the ventral striatum 
(9.5%) and the dorsal putamen (8.3%) in both groups (Spreckelmeyer et al. 2011).  We 
can expect similar reductions due to DA release after morphine in one or both research 
groups (118A homozygotes; 118GX).  A study that evaluated the effect of the variants of 
the OPRM1 genotype in social drinkers compared during placebo and alcohol infusions 
found a significantly greater DA release as measured by binding potential in those 
participants who carried the G allele (N=12) compared to the 118 homozygotes (N=16) 
(Ramchandani et al. 2011).  However, results of the studies in the humanized mouse 
strains of these two genotypes yielded opposite effects of genotype on DA release from 
morphine. 
If the results of this study yield similar results, 40 completers per group should provide 
adequate power to detect effects of OPRM1 genotype.  We estimate that to have this 
number of completers, we must screen and genotype at least 120 prospective participants. 
Accrual number request, taking into account screening/ dropouts   


 
 
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We are requesting an accrual limit of 120 to obtain 80 subjects to complete the study. 
Power Analysis: 
Analysis: 
A priori: Compute required sample size  
Input: 
Effect size f 
= 0.65 
 
α err prob 
= 0.05 
 
Power (1-β err prob) 
= 0.80 
 
Number of groups 
= 2 
Output: 
Noncentrality parameter λ 
= 9.2950000 
 
Critical F 
= 4.3512435 
 
Numerator df 
= 1 
 
Denominator df 
= 20 
 
Total sample size 
= 22 
 
Actual power 
= 0.8262998 
 
An effect size of Cohen’s F = .65 was observed by Ramchandani et al. (2011). To detect 
an effect size of Cohen’s F=0.65 with a 90% probability at an alpha=0.05, a total sample 
size of 24 would be required. To ensure adequate power to reliably detect somewhat 
smaller effect sizes, we will recruit a total sample size of 40 males per genotype. 
 
This result is based on the effect size in data acquired by Ramchandani et al. (2011) in a 
similar study in which the challenge was alcohol. 
11. Human Subjects Protection 
a. Subject selection 
This study will be conducted in healthy 21-55 year-old male participants. The 
specific inclusion and exclusion criteria are listed in a previous section.  
Females will not be recruited.  As this study aims to examine whether OPRM1 
A118G variation moderates the mesolimbic DA response to µ-opioid receptor 
activation, it is important that we have a signal that could be modified. Using non-
human primates, it was previously found that the rhesus ortholog of the human 
OPRM1 A118G SNP only moderated alcohol-induced psychomotor stimulation 


 
 
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(a marker of mesolimbic DA activation) in males but not in females (Barr et al. 
2007). This difference was presumably due to the negligible overall psychomotor 
response in the latter group. In agreement with those observations, a subsequent 
human PET study (Urban et al. 2010) found only marginal alcohol-induced DA 
release, (measured as % change in [11C]raclopride binding potential) in females 
while a robust response was present in males. Alcohol activates mesolimbic DA 
neurons indirectly, through release of endogenous opioids and their actions at µ-
opioid receptors (Heilig et al. 2011;Urban et al. 2010). Because endogenous 
opioid release in response to alcohol does not differ between men and women 
(Mitchell et al. 2012), it must be concluded that the observed sex differences are 
likely to be postsynaptic. A similar sexual dimorphism is therefore likely to exist 
for actions of an exogenous µ-opioid agonist. Taken together, these observations 
thus make it unlikely that the hypothesis of the present study can be addressed in 
females, providing a compelling scientific rationale for restricting recruitment to 
males. 
Participants will be recruited through advertisement in local media (electronic and 
print) at NIH and in the greater Baltimore and Washington DC areas. The study 
will be open to all racial and ethnic groups, without targeting any specific group.  
 
NIH TARGETED/PLANNED ENROLLMENT 
 
ETHNIC CATEGORY 
Sex/Gender 
Females 
Males 
Total 
Hispanic or Latino 
0 
9 
9** 
Not Hispanic or Latino 
0 
111 
111 
Ethnic Category: Total of All Subjects* 
0 
120 
120* 
RACIAL CATEGORIES 
0 
 
 
American Indian/Alaska Native 
0 
2 
2 
Asian 
0 
13 
13 
Native Hawaiian or Other Pacific Islander 
0 
1 
1 
Black or African American 
0 
14 
14 
White 
0 
90 
90 
Racial Categories: Total of All Subjects* 
0 
120 
120* 
*The “Ethnic Category: Total of All Subjects” must be equal to the “Racial Categories: total of All Subjects.” 
 
 
b. Justification for exclusion of children  
Studies involving radiation exposure are counter indicated in children under the 
age of 18 years.  Studies involving administration of opioids are counter indicated 
in children under the age of 21 years.  Therefore, only adult participants over age 
21 will be enrolled.  
APPROVED STUDY POPULATION 
 
FEMALE 
ENROLLMENT 
MALE 
ENROLLMENT 
TOTAL 
ENROLLMENT 
FEMALE 
COMPLETERS 
MALE 
COMPLETERS 
TOTAL 
COMPLETERS 
APPROVED 
CEILING 
0 
120 
120 
0 
80 
80 


 
 
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c. Justification for exclusion of other vulnerable subjects  
Vulnerable participants will not be enrolled.  
d. Justification of sensitive procedures  
To avoid an expectation effect the study will be run single blind.  The participant 
will be told that the injection on any given day may be active drug or placebo.  At 
the end of the study, the participant will be told when he received the active drug.  
e. Safeguards for vulnerable populations 
Women will not be recruited. 
f. Qualifications of investigators 
Vijay A. Ramchandani, Ph.D. is the Chief of the Section on Human 
Psychopharmacology in the Laboratory of Clinical and Translational Studies. He is a 
clinical pharmacologist with several years of experience conducting human laboratory 
studies, particularly using the alcohol infusion method, which he co-developed. He 
participated in the study design and protocol development, and will oversee the study 
conduct and analysis. Dr. Ramchandani will obtain consent for this study.  
Peter Herscovitch, MD, is Chief of the PET department in the Clinical Center of NIH. 
He has several years of experience in conducting imaging studies, including PET studies 
with radiotracers such as raclopride. He participated in study design and protocol 
preparation. 
Kenzie L. Preston, Ph.D., is Chief of the Treatment Section and Chief of the Clinical 
Pharmacology and Therapeutics Research Branch, NIDA IRP. Her undergraduate degree 
is a B.S. in pharmacy, and she is a registered pharmacist. The Archway clinic is part of 
the Clinical Trials Section and under the leadership of Dr. Preston. She has an established 
reputation in the field of opioid abuse research and is currently conducting a series of 
clinical trials of combination treatment including contingency management and 
buprenorphine maintenance.  She participated in study design and protocol preparation 
and will participate in manuscript preparation. 
Karran Phillips, M.D., M.Sc., is a Staff Clinician in the Treatment Section, NIDA IRP. 
She is Board Certified in Internal Medicine, fellowship-trained in General Internal 
Medicine, certified in Addiction Medicine, and completed a graduate degree in public 
health. She has clinical and research experience working with patients with substance 
dependence and HIV.  She will be the Medical Advisory Investigator (MAI), will 
supervise the medical aspects of the study, and will coordinate the medical care of 
patients when appropriate. She will administer the morphine dose at the BRC.  She will 
be in the room with the participant for at least 30 minutes following the morphine 
administration or until vital signs have returned to the normal range. She has current 
ACLS certification. She participated in study design and protocol preparation and will 
also participate in data analysis and manuscript preparation and has been designated by 
the PI to obtain consent.  
Elliot A. Stein, Ph.D., is a behavioral neuroscientist and Chief of the Neuroimaging 
Research Branch, NIDA-IRP. He has more than 20 years of experience in the 
neurophysiology and neuropharmacology of drugs of abuse. Dr. Stein will assume 


 
 
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responsibility for the supervision and performance of all MRI data analysis and 
interpretation. He will participate in data analysis and manuscript preparation.  
Primavera A. Spagnolo, M.D. is a post-doctoral fellow in the Section of Clinical 
Assessment and Treatment Evaluation, Laboratory of Clinical and Translational Studies, 
NIAAA/NIH. She is Board Certified in Addiction Medicine and Medical Toxicology. 
She has clinical and research experience working with patient with alcohol and substance 
dependence, especially in capacities involving direct patient care of opiate addicts. She 
will participate in overseeing the administration of morphine during the PET scans and 
assist with data analysis.  
Reza Momenan, PhD, is a staff scientist with the Section on Brain Electrophysiology 
and Imaging (SBEI), Laboratory of Clinical and Translational Studies, and currently its 
acting Chief. He has over 20 years of experience in conducting research in various 
medical imaging modalities. In the present study, he is working on experimental 
paradigm design and implementation, medical imaging, image analysis, and other data 
analysis.  He will not be obtaining consent. 
Nancy Diazgranados, M.D., M.S.  Dr. Diazgranados received her Doctoral Degree in 
Medicine and Surgery from the Pontificia Universidad Javeriana in Bogota Colombia in 
2001. She completed her Psychiatry residency at Albert Einstein Medical Center and a 
Master in Science Degree in Pharmacology at Thomas Jefferson University in 2007. In 
2008 she became a diplomate of the American Board of Psychiatry and Neurology. She 
continued her training as a Post-Doctoral Clinical-Research Fellow at the intramural 
program at NIMH; there she worked at the Experimental Therapeutics and 
Pathophysiology Branch in the Mood and Anxiety Disorders Program.  In 2010 she 
joined the University of Texas Health Science Center at San Antonio as a tenure track 
assistant professor within the Division of Mood and Anxiety Disorders. In 2012 she 
joined a private practice and relocated to Maryland. Finally in September 2013 she joined 
NIAAA as a staff clinician. She will administer the morphine dose for the PET studies at 
the NIH CC and supervise the procedure until the participant is medically cleared. She is 
an NIH credentialed physician with current ACLS certification. 
Michelle Leff, M.D., M.B.A. Dr. Leff is the Chief of Staff at the NIDA IRP.  She is 
board-certified in General Psychiatry and Child/Adolescent Psychiatry.  She has served 
as the MAI on various IRP protocols, including treatment studies for adolescent smokers, 
and served as the Deputy Clinical Director from 2003-2011.  She is NIH-credentialed and 
JHBMC-credentialed, and is ACLS-certified.  She will provide ad hoc coverage for the 
MAI. 
12. Anticipated Benefit 
This study does not offer direct medical or health benefit to participants but is likely to 
yield generalizable knowledge about the effects of opioids and their potential for abuse 
by determining the effect of an opiate on dopamine release in the brain, and the role of 
the opioid receptor (OPRM) polymorphism on this response in humans. 
13. Summary/ classification of risk:  
This study is classified as “more than minimal risk”. 


 
 
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The overall risk of participation in this study is low, and every precaution and protection 
to minimize any risks will be taken as described in a previous section. The study is 
expected to provide important information about the pharmacological effects of opiates, 
and the role of the opioid receptor (OPRM1) polymorphism, in humans. We believe the 
benefit:risk ratio of the proposed study is favorable. 
14. Consent documents and process 
a. Designation of those obtaining consent 
Study investigators designated as able to obtain consent in section 11f above will obtain 
informed consent.  
b. Consent procedures  
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.  
c. Consent documents 
The consent form contains all required elements.  We will use an “Evaluation to Sign 
Consent” which has been tailored to this protocol in lieu of a consent quiz as the method 
to ensure participant understanding of the study.   
15. Data and Safety monitoring 
a. Data and Safety Monitor 
This is a small, single-site Phase 2a / physiologic study of short duration. It is carried out 
in healthy research volunteers, a population that is neither vulnerable, nor at elevated risk 
for death or other serious outcomes. The study involves administration of morphine, an 
FDA approved medication, at a dose that is at the high end, but within the range of what 
is recommended on the FDA approved label. Accordingly, previous studies administering 
this dose to healthy research volunteers have not reported any serious adverse events.  
Although the study therefore does not meet any of the FDA criteria (FDA 2013) for the 
need for a Data Safety and Monitoring Board (DSMB), we will utilize the standard 
DSMB for protocols reviewed by the Addictions IRB.  The Principal Investigator and 
Medical Advisory Investigator will also monitor the study.   
b. Data and safety monitoring plan 
Data and safety monitoring will be done by the PI, the MAI, and the DSMB for 
Addictions IRB, which will have access to unblinded data. 
Data to be monitored   
1) Participant accrual 
2) Safety data 
3) Adverse events; serious, nonserious, expected, and unexpected 
4) Study dropout, including the reason(s) for dropout (adverse 
event, treatment failure, etc.) 
Materials submitted to the DSMB 


 
 
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In addition to the materials identified above that will be sent to the monitor for 
regularly scheduled reviews, we will report protocol-related serious, unexpected 
adverse events to the monitor at the same time that we report them to the IRB, the 
Clinical Director, and other NIH officials.  Additionally, we will notify the 
monitor promptly of any protocol amendments. 
Interim Analyses 
An interim analysis of the PET data is planned after the first 5 participants in each 
group.  The purpose of this analysis is to ensure that dopamine release as 
evidenced by a reduction in binding potential for [11C]raclopride by the morphine 
challenge is observed, at least in those participants who are homozygous for the A 
allele.  If no participant (regardless of genotype) exhibits dopamine release, the 
study will be stopped.  If an alternative approach to the study is deemed more 
likely to allow the measurement dopamine release, such as the use of a different 
opiate drug or different radioligand, a revised protocol may be submitted. 
DSMB Reports 
The DSMB will make findings and interpret the data, then report to the PI, IRB, 
and Clinical Director about continuation, modification, suspension, or termination 
of the protocol based on observed beneficial or adverse effects of the 
experimental treatment under study.  The DSMB will act promptly on any 
findings indicating the need for an amendment to the protocol or affecting the 
continuation of the protocol. 
Review Schedule 
The DSMB will examine the safety data after the first 10 participants have 
completed the study. Additional reviews will occur each time the number of study 
completers (or dropouts) has increased by 20.  Additional reviews will be 
conducted if warranted by the occurrence of serious adverse events or otherwise 
deemed necessary by the DSMB. 
c. Criteria for stopping the study or suspending enrollment or procedures 
The study will be stopped after we complete data collection from our target 
number (80) of participants who complete the study.  The study will be stopped 
prior to that point if an interim analysis does not show any effect of the opiate 
administration on the release of dopamine.  If there are any serious adverse events 
following the administration of the opiate that are found to be protocol related, the 
protocol will be suspended until the safety of continuing the protocol can be 
established or stopped if the safety of continuing the protocol cannot be 
established.  
16. Quality Assurance 
a. 
Quality assurance monitor 
The Principal Investigator, Lead Investigator and the MAI will be monitoring data 
collection and the study on an ongoing basis.  Quality assurance (QA) will be performed 
by NIDA QA and NIAAA QA staff as indicated in the NIDA and NIAAA Quality 
Assurance Monitoring Planas described below. 
b. 
Quality assurance plan 
Quality assurance, including monitoring of Compliance with Good Clinical Practice 


 
 
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standards, will be carried outby NIDA and NIAAA QA staff. Monitors will review 
individual Clinical Research Files and establish their agreement with relevant source 
documents, will review the study Regulatory Binder for completeness and relevant 
updates, and will confirm compliance with all regulatory requirements including 
appropriate reporting of AE’s. Monitors will bring any deficiencies encountered to the 
attention of the PI,and will follow up on these through resolution.  
17. Adverse event reporting 
Serious or unexpected adverse events and other unanticipated problems will be reported 
orally as soon as possible and in writing within 7 days if life-threatening and within 15 
days otherwise.  Expected or non-serious adverse events will be reported at the time of 
continuing review. 
18. Alternatives to participation or alternative therapies 
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. Confidentiality 
This protocol is covered by a Certificate of Confidentiality issued by the US Department 
of Health and Human Services.  Strict subject confidentiality will be maintained 
throughout the study. Confidentiality and information technology standards are in place 
at the NIAAA/LCTS and NIDA intramural programs to protect electronic repositories of 
patient data as well as other clinical patient related material. It is reasonably expected that 
these safeguards will protect participants' medical and personal health information, 
ensuring their privacy.   
Information obtained in the course of being screened for or participating in this protocol 
will become part of the patient's NIH medical record. This includes potentially sensitive 
information, such as urine tests positive for illicit drugs. Access to this information may 
be requested by third parties. Such access will not be granted without the explicit, written 
consent of the subjects. However, failure on the part of the subject to provide access to 
the information may in itself be to the disadvantage of the subject, e.g. in the case of a 
potential employer or insurer requesting the information. This situation will be made 
clear in the consent. 
Samples and data will be stored using codes that we assign.  Data will be kept in 
password protected computers.  Samples will be kept in locked storage.  Only study 
personnel will have access to the samples and data. 
20. Conflict of Interest 
Statement of conflict of interest of investigators:  
NIH guidelines on conflict of interest have been distributed to all investigators. There are 
no conflicts-of-interest to report.  There is no commercial sponsor or company for this 
study. 
 
 


 
 
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21. Technology Transfer 
List tech transfer agreement/s and confidential disclosure agreements:  
Agreement type and number ____#30749-10_____ Expiration Date_ July 29, 2016___ 
with University of Memphis to cover the AutoSense in the opiate PET study  
 
Statement of the role of the drug company:  
These data collected during administration of morphine under controlled laboratory 
conditions will be used to develop an algorithm to detect opioid administration in future 
field studies.  De-identified data from the AutoSense and age, gender, and drug use 
history will be sent to Dr. Kumar at the University of Memphis (Material Transfer 
Agreement #30749-10; expiration date 7/29/2016) and to Dr. Yixin Chen at Washington 
University for analysis.. 
22. Research and Travel Compensation  
Participants will receive compensation according to the NIH guidelines for payment 
to normal volunteers.  Participants will receive $1362.50 for completion of the three 
injection sessions of the study, as described below. In addition, participants will 
receive compensation for the screening evaluation under the screening protocol. The 
following table gives the breakdown of procedures (duration and inconvenience units) 
used in computation of the compensation.  If participants are unable to complete the 
study, they will be paid on a pro-rated (meaning partial payment) basis.  Travel to and 
from the clinic and meals will be covered during their visits to the clinic. 
Procedure 
Amount 
Visit 1 – Study consent interview, questionnaires 
$112.50 
MRI 
$75* 
Visit 2: IV catheter insertion, morphine injection, blood 
draws, testing, physiological monitoring with AutoSense 
$300 
Visit 3: overnight stay, multiple IV catheter insertion, C-11 
raclopride and morphine/placebo injection, blood draws, 
testing 
$350 
Visit 4: overnight stay, multiple IV catheter insertion, C-11 
raclopride and morphine/placebo injection, blood draws, 
testing, safety assessment including physical exam, EKG, 
CBC and blood chemistry.  
$400 
Completion incentive 
$125 
TOTAL 
$1362.50 
*If the MRI is not acquired under protocol 10-DA-N457 


 
 
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Appendix I - Questionnaires 
Previous experience with pain pills: 
 
Drug taken (please check those you have taken:  
___Codeine 
___Demerol  
___Lorcet  
___Vicodin  
___Lorcet Plus  
___Vicodin ES  
___Norco  
___Lortab  
___Vicodin HP  
___Percocet  
___Percodan  
___Oxycontin 40  
___RMS MS Contin  
___Duragesic 
___Fentora 
___Actiq  
___Dilaudid (tabs) 
___Palladone (caps)  
___Opana 
___Opana ER  
___Oxycotin 
___oxycodone 
___Other____________ 
 
 
Please indicate why you were prescribed this medication: 
________________________________________________________________________ 
________________________________________________________________________ 
________________________________________________________________________ 
________________________________________________________________________ 
 
When did you take this medication (month, year)? ________________________ 
 
How long did you take this medication?   ____ days  _______ months  _______ years 
 
When did you stop taking this medication?  ___________________ 


 
 
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Please rate whether you experienced the following effects when you have used pain pills in the 
past and how much you felt this effect.  List is adapted from Apfelbaum et al. (2004) 
 
Relaxed 
(1) 
(2) 
(3) 
(4) 
(5) 
(6) 
(7) 
(8) 
(9) 
(10) 
 
 
No effect 
 
 
 
 
 
 
very relaxed 
 
Drowsiness 
(1) 
(2) 
(3) 
(4) 
(5) 
(6) 
(7) 
(8) 
(9) 
(10) 
Not drowsy 
 
 
 
 
 
 
Fell asleep 
 
Dizziness 
(1) 
(2) 
(3) 
(4) 
(5) 
(6) 
(7) 
(8) 
(9) 
(10) 
 
Not dizzy 
 
 
 
 
 
 
Felt very dizzy 
 
Nausea 
(1) 
(2) 
(3) 
(4) 
(5) 
(6) 
(7) 
(8) 
(9) 
(10) 
 
 
Not nauseous   
 
 
 
 
 
Vomited a lot 
 
 
Pain Relief 
(1) 
(2) 
(3) 
(4) 
(5) 
(6) 
(7) 
(8) 
(9) 
(10) 
 
 
No relief 
 
 
 
 
 
 
Pain gone 
 
Constipation (1) 
(2) 
(3) 
(4) 
(5) 
(6) 
(7) 
(8) 
(9) 
(10) 
 
 
None  
 
 
 
 
 
Needed Medication 
 
Trouble breathing  (1) (2) 
(3) 
(4) 
(5) 
(6) 
(7) 
(8) 
(9) 
(10) 
 
 
No trouble breathing  
 
 
 
very short of breath 
 
Itching  
(1) 
(2) 
(3) 
(4) 
(5) 
(6) 
(7) 
(8) 
(9) 
(10) 
 
 
No itching 
 
 
 
 
couldn’t stop scratching 
 
Dry mouth 
(1) 
(2) 
(3) 
(4) 
(5) 
(6) 
(7) 
(8) 
(9) 
(10) 
 
 
Not experienced 
 
 
 
 
        very dry mouth 


 
 
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Now, please rate whether you considered this effect good, bad or of no concern 
 
Relaxed 
 
good  
no concern 
 
bad 
 
Drowsiness 
 
good  
no concern 
 
bad 
 
Dizziness 
 
good  
no concern 
 
bad 
 
Nausea 
 
good  
no concern 
 
bad 
 
Pain Relief 
 
good  
no concern 
 
bad 
 
Constipation  
good  
no concern 
 
bad 
 
Trouble breathing  
good  
no concern 
 
bad 
 
Itching  
 
good  
no concern 
 
bad 
 
Dry mouth 
 
good  
no concern 
 
bad 
 
 
 
 


 
 
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The DEQ consists of four visual analog scales used to describe current drug effects. Subjects 
mark on 100-mm lines whether they  
 
(1) feel drug effects  
0          x          x          x          x          x          x          x          x          x          100 
None  
 
 
 
 
 
 
 
 
a lot 
 
(2) like the effects they feel  
0          x          x          x          x          50          x          x          x          x          100 
Dislike  
 
 
 
neutral  
 
 
 
like extremely 
 
(3) feel high  
0          x          x          x          x          x          x          x          x          x          100 
not at all 
 
 
 
 
 
 
 
 
a lot 
 
(4) would like more  
0          x          x          x          x          x          x          x          x          x          100 
not at all 
 
 
 
 
 
 
 
 
a lot 


 
 
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Likert-like visual analog scale (VAS) of common side effects of opiate administration. 
Sedation 
(1) 
(2) 
(3) 
(4) 
(5) 
(6) 
(7) 
(8) 
(9) 
(10) 
 
 
No effect 
 
 
 
 
 
 
very relaxed 
 
Drowsiness 
(1) 
(2) 
(3) 
(4) 
(5) 
(6) 
(7) 
(8) 
(9) 
(10) 
Not drowsy 
 
 
 
 
 
 
Fell asleep 
 
Dizziness 
(1) 
(2) 
(3) 
(4) 
(5) 
(6) 
(7) 
(8) 
(9) 
(10) 
 
Not dizzy 
 
 
 
 
 
 
Felt very dizzy 
 
Upset stomach 
(1) 
(2) 
(3) 
(4) 
(5) 
(6) 
(7) 
(8) 
(9) 
(10) 
 
 
Not nauseous   
 
 
 
 
 
Vomited a lot 
 
Trouble breathing  (1) (2) 
(3) 
(4) 
(5) 
(6) 
(7) 
(8) 
(9) 
(10) 
 
 
No trouble breathing  
 
 
 
very short of breath 
 
Itching  
(1) 
(2) 
(3) 
(4) 
(5) 
(6) 
(7) 
(8) 
(9) 
(10) 
 
 
No itching 
 
 
 
 
couldn’t stop scratching 
 
Dry mouth 
(1) 
(2) 
(3) 
(4) 
(5) 
(6) 
(7) 
(8) 
(9) 
(10) 
 
 
Not experienced 
 
 
 
 
        very dry mouth 
 
Headache 
(1) 
(2) 
(3) 
(4) 
(5) 
(6) 
(7) 
(8) 
(9) 
(10) 
 
 
No effect 
 
 
 
 
 
 
bad headache 
 
Euphoria 
(1) 
(2) 
(3) 
(4) 
(5) 
(6) 
(7) 
(8) 
(9) 
(10) 
 
 
No effect 
 
 
 
 
 
 
very high 
 
Anxiousness (1) 
(2) 
(3) 
(4) 
(5) 
(6) 
(7) 
(8) 
(9) 
(10) 
 
 
No effect 
 
 
 
 
 
 
very anxious 
 
Depression 
(1) 
(2) 
(3) 
(4) 
(5) 
(6) 
(7) 
(8) 
(9) 
(10) 
 
 
No effect 
 
 
 
 
 
 
felt very sad 
 
Tremors  
(1) 
(2) 
(3) 
(4) 
(5) 
(6) 
(7) 
(8) 
(9) 
(10) 
 
 
No effect 
 
 
 
 
 
 
shaking a lot 
 
 
 


 
 
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Abbreviated Comprehensive Psychopathology Rating Scales (NIAAA/LCTS version) 
Patient’s Name:  
 
 
Patient’s MRN:  
 
Date and Time: 
1. Reported sadness 
Representing reports of depressed mood, regardless of whether it is reflected in appearance or not.  
Includes low spirits, despondency or the feeling of being beyond help and without hope. 
Rate according to intensity, duration and the extent to which the mood is reported to be influenced by 
events. 
0 = Occasional sadness in keeping with the circumstances. 
1 
2 = Sad or low but brightens up without difficulty. 
3 
4 = Pervasive feelings of sadness or gloominess. The mood is still influenced by external 
circumstances. 
5 
6 = Continuous or unvarying sadness, misery or despondency. 
2. Inner tension 
Representing feelings of ill-defined discomfort, edginess, inner turmoil, mental tension mounting to either 
panic, dread or anguish. 
Rate according to intensity, frequency, duration and the extent of reassurance called for. 
0 = Placid. Only fleeting inner tension. 
1 
2 = Occasional feelings of edginess and ill-defined discomfort. 
3 
4 = Continuous feelings of inner tension or intermittent panic which the patient can only master with some 
difficulty. 
5 
6 = Unrelenting dread or anguish. Overwhelming panic.  
3. Hostile feelings 
Representing anger, hostility and aggressive feelings regardless of whether they are acted or not. 
Rate according to intensity, frequency and the amount of provocation tolerated. 
0 = Not easily angered. Inability to feel anger. 
1 
2 = Easily angered. Reports hostile feelings which are easily dissipated 
3 
4 = Reacts to provocation with excessive anger and hostility 
5 
6 = Persistent anger, rage or intense hatred which difficult or impossible to control 
4. Inability to feel 
Representing the subjective experience of reduced interest in the surroundings, or activities that normally 
give pleasure. The ability to react with adequate emotion to circumstances or people is reduced. 
0 = Normal interest in the surroundings and in other people. 
1 
2 = Reduced ability to enjoy usual interests. 
3 
4 = Loss of interest in the surroundings. Loss of feelings for friends and acquaintances. 
5 
6 = The experience of being emotionally paralyzed, inability to feel anger, grief or pleasure and a 
complete or even painful failure to feel for close relatives and friends.  


 
 
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5. Pessimistic thoughts 
Representing thoughts of guilt, inferiority, self-reproach, sinfulness, remorse and ruin. 
0 = No pessimistic thoughts. 
1 
2 = Fluctuating ideas of failure, self-reproach or self-depreciation. 
3 
4 = Persistent self-accusations, or definite but still rational ideas of guilt or sin. Increasingly pessimistic 
about the future 
5 
6 = Delusions of ruin, remorse or unredeemable sin. Self-accusations which are absurd and unshakable.  
6. Suicidal thoughts 
Representing the feeling that life is not worth living, that a natural death would be welcome, suicidal 
thoughts, and preparations for suicide. Suicidal attempts should not in themselves influence the rating. 
0 = Enjoys life or takes it as it comes. 
1 
2 = Weary of life. Only fleeting suicidal thoughts. 
3 
4 = Probably better off dead. Suicidal thoughts are common, and suicide is considered as a possible 
solution, but without specific plans or intention. 
5 
6 = Explicit plans for suicide when there is an opportunity. Active preparations for suicide.  
7. Hypochondriasis 
Representing exaggerated preoccupation or unrealistic worrying about ill health or disease. Distinguish 
from worrying over trifles and aches and pains. 
0 = No particular preoccupation with ill health 
1 
2 = Reacting to minor bodily dysfunction with foreboding. Exaggerated fear of disease. 
3 
4 = Convinced that there is some disease but can be reassured, if only briefly. 
5 
6 = Incapacitating or absurd hypochondriacal convictions (body rotting away, bowels have not worked for 
months)  
8. Worrying over trifles 
Representing apprehension, and undue concern over trifles, which is difficult to stop and out of proportion 
to the circumstances. Distinguish from inner tension, pessimistic thoughts, hypochondiasis and phobias. 
0 = No particular worries 
1 
2 = Undue concern, worrying that can be shaken off 
3 
4 = Apprehensive and bothered about trifles or minor daily routines 
5 
6 = Unrelenting and often painful worrying. Reassurance is ineffective 
9. Phobias 
Representing feelings of unreasonable fear in specific situations (such as buses, supermarkets, crowds, 
feeling enclosed, being alone) which are avoided if possible. 
0 = No phobias 
1 
2 = Feelings of vague discomfort in particular situations which can be mastered without help or by taking 
simple precautions like avoiding rush hours when possible 
3 
4 = Certain situations consistently provoked marked discomfort, and are avoided without impairing social 
performance 
5 
6 = Incapacitating phobias which severely restrict activities, for example completely unable to leave home 


 
 
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10. Lassitude 
Representing a difficulty getting started or slowness initiating and performing everyday activities. 
0 = Hardly any difficulties in getting started. No sluggishness. 
1 
2 = Difficulties in starting activities 
3 
4 = Difficulties in starting simple routine activities which are carried out with effort. 
5 
6 = Complete lassitude. Unable to do anything without help.  
11. Concentration difficulties 
Representing difficulties in collecting one's thoughts mounting to incapacitating lack of concentration. 
Rate according to intensity, frequency, and degree of incapacity produced. 
0 = No difficulties in concentrating. 
1 
2 = Occasional difficulties in collecting one's thoughts. 
3 
4 = Difficulties in concentrating and sustaining thought which reduces ability to read or hold a 
conversation. 
5 
6 = Unable to read or converse without great difficulty.  
12. Reduced appetite 
Representing the feeling of a loss of appetite compared with when well.  Rate by loss of desire for food or 
the need to force oneself to eat. 
0 = Normal or increased appetite 
1 
2 = Slightly reduced appetite. 
3 
4 = No appetite. Food is tasteless. 
5 
6 = Needs persuasion to eat at all.  
13. Reduced sleep 
Representing the experience of reduced duration or depth of sleep compared to the subject's own normal 
pattern when well. 
0 = Sleeps as usual. 
1 
2 = Slight difficulty dropping off to sleep or slightly reduced, light or fitful sleep. 
3 
4 = Sleep reduced or broken by at least two hours. 
5 
6 = Less than two or three hours sleep.  
14. Autonomic disturbances 
Representing descriptions of palpitations, breathing difficulties, dizziness, increased sweating, cold hands 
and feet, dry mouth, indigestion, diarrhea, frequent micturition. Distinguish from hypochondriasis, 
autonomic disturbance (item 18), and muscular tension. 
0 = No autonomic disturbances 
1 
2 = Occasional autonomic symptoms which occur under emotional stress 
3 
4 = Frequent or intense autonomic disturbances which are experienced as discomforting or socially 
inconvenient 
5 
6 = Very frequent autonomic disturbances which interrupt other activities or are incapacitating.  


 
 
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15. Aches and pains 
Representing reports of bodily discomfort, aches and pains. Rate according to intensity, frequency and 
duration, and also request for relief. Disregard any opinion of organic cause. Distinguish from 
hypochondriasis, autonomic disturbance, and muscular tension. 
0 = Absent or transient 
1 
2 = Occasional definite aches and pains 
3 
4 = Prolonged and inconvenient aches and pains. Requests for effective analgesics 
5 
6 = Severely or crippling pains 
16. Muscular tension 
Representing observed muscular tension as shown in facial expression, posture, and movements. 
0 = Appears relaxed 
1 
2 = Slightly tense posture and face. 
3 
4 = Moderately tense posture and face (easily seen in jaw and neck muscles). Does not seem to find a 
relaxed position when sitting. Stiff and awkward movements 
5 
6 = Strikingly tense. Often sits hunched and crouched, or tense and rigidly upright at the edge of the chair 
17. Apparent Sadness 
Representing despondency, gloom and despair, (more than just ordinary transient low spirit) reflected in 
speech, facial expression, and posture.  Rate by depth and inability to brighten up. 
0 = No sadness. 
1 
2 = Looks dispirited but does brighten up without difficulty. 
3 
4 = Appears sad and unhappy most of the time. 
5 
6 = Looks miserable all the time. Extremely despondent 
18. Autonomic disturbances 
Representing signs of autonomic dysfunction, hyperventilation or frequent sighing, blushing, cold hands, 
enlarged pupils and dry mouth, fainting. 
0 = No observed autonomic disturbances 
1 
2 = Occasional or slight autonomic disturbances such as blushing or blanching, or sweating under stress 
3 
4 = Obvious autonomic disturbance on several occasions even when not under stress 
5 
6 = Autonomic disturbances which disrupt the interview 


 
 
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Items used in scoring Depression (MADRS) and Anxiety (BSA) 
Depression 
- Reported sadness (Item #1) 
- Inner tension (Item #2) 
- Inability to feel (Item #4) 
- Pessimistic thoughts (item #5) 
- Suicidal thoughts (item #6) 
- Lassitude (item #10) 
- Concentration difficulties (item #11) 
- Reduced appetite (item #12) 
- Reduced sleep (item #13) 
- Apparent Sadness (CPRS item #17) 
Anxiety 
- Inner tension (Item #2) 
- Hostile feelings (Item #3) 
- Hypochondriasis (item #7) 
- Worrying over trifles (item #8) 
- Phobias (item #9) 
- Reduced sleep (item #13) 
- Autonomic disturbances (reported) (item #14) 
- Aches and pains (item #15) 
- Muscular tension (item #16) 
- Autonomic disturbances (observed) (item #18) 
Note that items #2 (inner tension) and #13 (reduced sleep) contribute to the score for both indexes 
(MADRs and BSA) 
 
 


 
 
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Cold Pressor Test – Pain scoring 
 
How does your hand in the water bath feel right now? 
 
       0           1           2           3            4            5           6           7            8           9 
      I- - - - - I- - - - - I- - - - - I- - - - - I- - - - - I- - - - - I- - - - - I- - - - - I- - - - - I 
discomfort   mild           moderate         intense          extreme        excruciating          unbearable 
                     pain                 pain                 pain                 pain                   pain                        pain 
 
Hand withdrawn:    ___min  ____sec (Max 3 min) 
 
 


 
 
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Appendix II. Recruiting advertisements 
1) Kimes_Opiod Pills Protocol_ DRAFT Ad 
The ad will include a standard NIDA graphic and the following text. 
 
If you … 
▪ Are healthy and between 21 – 55 
▪ Have ever used pain pills for a medical condition such as a broken bone or dental surgery 
▪ Are a non-smoker 
… we need YOU for a research study in East Baltimore.  
The purpose of this research is to test the effect of genetics and a pain reducing medication on 
receptors for a brain molecule called dopamine.    
There is no cost to participate 
▪ If selected, you will be compensated for your participation in this study. 
Call today for a confidential screening. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
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Appendix III. Screening questionnaires for Patient 
Recruitment Office 
The following provides the stepwise participant screening procedure for this protocol. 
Advertisements for this protocol are placed under the MMG contract.  The prospective 
participants call a phone number that is answered by MMG Recruitment staff.  The standard, 
approved phone screening consent form is used.  If the initial phone screen indicates that the 
prospective participant is eligible for participation in this study, he is invited to NIDA for the rest 
of the screening procedure.  Participant is excluded if he is younger than 21 yrs or older than 55 
yrs.  
The prospective participant comes to the MMG recruitment reception area.  One of the recruiters 
explains the screening process to the person and obtains his consent for the screening process. . 
All clinical assessments/procedures will be carried out by an appropriately trained staff member. 
 
1) Psychological and Psychosocial Testing 
a. Shipley Institute of Living Scales or Vocabulary module of WASI (Wechsler Abbreviated 
Scale of Intelligence).  
b. All subjects must have a stable point of contact. 
c. Edinburgh Handedness Inventory – Subjects undergoing PET scans must be right handed. 
d. SCID Screen Patient Questionnaire – Extended (SSPQ-X) Prospective participants are 
excluded if they present with any current DSM-IV axis I diagnosis, including substance use 
disorders (except nicotine dependence for either group).  Subjects may not be dependent on 
alcohol or caffeine. Occasional marijuana use is allowed and is defined as less than or equal 
to two cigarettes or blunts/month. 
e. Participant is excluded if there is claustrophobia.  To further exclude this possibility, all 
potential participants will be placed in the mock scanner for at least 5 min. 
2) Clinical Laboratory Testing 
A trained medical staff must perform the blood collection. The collection site will 
generally be the middle arm veins.  Notify the MAI of any values outside the normal 
range.  The MAI will make determination of participant’s suitability for the study.   
1. Chemistry 
a. 
Liver function: The acceptable upper limits are as follows: 
i. 
AST, ALT > 100 
ii. 
GGT twice the upper limit of normal 
2. Exclusionary Criteria for Other Laboratory Studies 
a. 
Potassium < 3.5 > 5.1 
b. 
BUN > 35 
c. 
Creatinine > 1.5 
d. 
Glucose > 125 fasting 
e. 
Total bilirubin > 2.0 
f. 
Calcium < 8.0 > 10.5 
3. Complete blood count - Results should be generally within or close to the normal ranges 
– Notify MAI of any values outside the normal range.  MAI will make determination of 
participant’s suitability for the study.   
a. 
Hematocrit: < 39% exception: hemoglobin thalassemia trait is present where 
hematocrit of 35% would be minimum acceptable value. 
b. 
White blood cell count must be between 3,500 and 11,500. 


 
 
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4. Urinalysis - Results should be generally within or close to the normal ranges – Notify 
MAI of any values outside the normal range.  MAI will make determination of 
participant’s suitability for the study.    
a. Protein of greater than or equal to 1+ 
b. Glucose of greater than or equal to 1+ 
5. Urine toxicology – There should be no positive results.  
6. Tuberculin skin testing (unless documented prior positive response, see Tuberculosis 
Policy). – Test results must be negative. 
7. HIV, Hepatitis B SAg, & hepatitis C –Results should be negative. 
3) History and Physical: A complete history and physical examination must be obtained on all 
applicants who wish to participate in this protocol.  Presentation of false medical information 
may be grounds for dismissal from study participation.  History to include the following – 
Except those items for which exclusion criteria are noted, MAI to review results and decide if 
participant must be excluded. 
A. History 
1. General:  
a.Recent unexplained weight loss greater than 10 lbs. in a 3-month period 
b.Fever of unexplained origin or a fever of greater than a one-month duration 
c.Unexplained night sweats 
d.History of malignancy 
e. 
Participant is excluded if he has ferromagnetic metal in the body or heart 
pacemaker  
f.Participant is excluded if he weighs more than 300 lbs. 
g.Participant is excluded if veins are inaccessible 
h.Radiation exposure from research studies exceeding 5.0 rem in the past 12 months 
i.Known chronic renal or hepatic dysfunction 
2. Cardiac: Participant excluded if he has a history of: 
a. Known arrhythmia 
b. Symptomatic or known coronary artery disease 
c. History of endocarditis, cerebral embolism 
3. Pulmonary: Participant excluded if he has a history of: 
a. Adult asthma – unless mild and occasional. 
b. History of obstructive pulmonary disease 
4. Neurological: Participant excluded if he has a history of: 
a. Structural brain abnormalities 
b. Infectious disease 
c. Head trauma resulting in unconsciousness greater than 5 minutes or hospitalization 
d. History of seizures as an adult 
e. Sleep apnea 
f. Tic disorder 
g. Autoimmune disease involving CNS 
5. Endocrine: Participant excluded if he has a history of: 
a. Hyperthyroidism 
b. Hypothyroidism 
c. Diabetes mellitus 
d. Endocrine disease 


 
 
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6. Current or Past Medication use:  Volunteers may not be currently using chronic 
prescription or over the counter medications.   
B. Physical Examination: 
1. 
Vital Signs 
a. 
Participant excluded if: Systolic blood pressure over 135 mm Hg or less than 95 
mm hg; diastolic blood pressure over 90 mm Hg, recorded on at least 3 different 
occasions. 
b. 
Participant excluded if: Pulse rate over 105 or less than 50 on a consistent basis. 
Irregular pulse rate should be evaluated with a 12 lead ECG and 3-5 minute 
rhythm strip that will become a part of the permanent record. 
c.Participant excluded if: Respiratory rate over 24 
2. 
Cardiac: Participant excluded if he has: 
a.Jugular venous distention 
b.Carotid bruits 
c.S3 and S4 heart sound 
d.Displaced point of maximal impulse, beyond the anterior axillary line 
e.Valvular disease 
f.Palpable thrill 
g.Peripheral edema 
3. 
Pulmonary: Participant excluded if he has: 
a.Wheezes, rales or rhonchi 
b.Cyanosis 
4. 
Diagnostic Studies - MAI to review results and decide if participant must be excluded. 
a.Electrocardiogram:  
All participants screened for non-therapeutic studies will have a 12 lead EKG and a 3 to 5 
minute rhythm strip done that will become a part of the permanent medical record. 
Participant is excluded if any of the following conditions are documented on an EKG: 
i.Wolfe Parkinson White syndrome 
ii.Myocardial infarction 
iii.Left bundle branch block, complete or partial 
iv.PR interval of less than .12 seconds or over .20 seconds 
v.Prolonged QT interval (corrected) greater than 0.43 seconds 
MMG Recruiting staff assigns ARC #s for the participant, prepares the charts and informs the 
MAI of the prospective participant.  
 
 


 
 
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Appendix IV. Investigator’s Brochure  
– none available for [11C]raclopride 
– See attached file of Morphine Package insert 
 
 


 
 
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Appendix VI. Other – Evaluation to sign consent and 
expected answers 


 
 
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 NIDA/NIAAA Evaluation of Potential Research Participants’ Ability to Consent 
ARC#: __ __ __ __ __ __Protocol #:  __________  Subject Initials:  ___ ___ Date:  ____/____/____ 
For each question, circle the score that most closely reflects your evaluation.          
You may explain or rephrase questions to help the potential participant understand them. Individuals 
who do not pass the first time may be re-evaluated once. 
 
Is the potential participant able to communicate, oriented,  
and not under the influence of drugs or alcohol? [if presently not 
capable, may be re-assessed later] 
0= Not Capable 
1= Capable 
 
 
 
1. What will you be asked to do if you enroll in the study?  
[must understand primary procedures] 
0 = no or insufficient 
understanding 
1 = sufficient 
understanding 
 
 
 
2. What are the most significant risks to you of being in the  
study? [must recognize the most significant risks] 
0 = no or insufficient 
understanding  
1 = sufficient 
understanding 
 
 
  
3.What happens if you don’t want to be in the study? [must 
understand that can decline without penalty] 
0 = no or insufficient 
understanding 
1 = sufficient 
understanding 
 
 
 
4. If you enroll in the study, can you later change your mind  
and stop participating? [must understand that can stop participating  
at any time] 
0 = no or insufficient 
understanding 
1 = sufficient 
understanding 
 
 
 
5. What are the chances that being in the study will benefit  
you personally? [must understand the potential benefits, including the 
possibility that will not benefit personally] 
0 = no or insufficient 
understanding 
1 = sufficient 
understanding 
 
 
 
6. What would you do if you experience pain or distress while 
in the study? [must be willing to tell team] 
0 = no or insufficient 
understanding 
1 = sufficient 
understanding 
 
 
 
7. What things could you do (for your condition) besides being
the study? [must recognize available alternatives]  
0 = no or insufficient 
understanding 
1 = sufficient 
understanding 
 
 
 
8. How do the risks and potential benefits of being in the  
study compare to the risks and benefits of your every day life. 
 [must understand comparative risks and potential benefits]]? 
0 = no or insufficient 
understanding 
1 = sufficient 
understanding 
 
 
 
9. For what reasons could we decide that you will not finish the  
study? 
0 = no or insufficient 
understanding 
1 = sufficient 
understanding 
 
I hereby certify that the potential participant has the ability to consent and scored 1 on all questions 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
________________________(Evaluator Signature)      __ __/__ __/__ __ __ __  (Date) 
 
 


 
 
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Appendix VII. Results from mouse study 
 
Individual probe placements in the nucleus accumbens (NAc) and dialysate DA levels in response to 
systemic morphine (3’ 10 and 30 mg/kg, i.p.) in h/mOPRM1-118AA and h/mOPRM1-118GG mice. 
Repeated measures ANOVA (with genotype as a between-factor and drug doses and time as within-factors) 
conducted for DA time course data showed significant main effect of dose (F(3,6) = 34.6; p < 0.001) and 
genotype (F(1,6) = 8.98; p = 0.024), indicating that NAc DA increased dose-dependently following morphine 
injections and overall response was different between two genotypes. Repeated measures ANOVA 
(genotype – between-factor, dose – within-factor) conducted for area under the curve (AUC) DA data 
revealed significant main effect of genotype (F(1,14) = 4.38; p = 0.05) and dose x genotype interaction (F(2,14) 
= 4.06; p = 0.037), as well as significant simple effect of genotype for DA response to the second drug dose 
(F(1,14) = 7.31; p = 0.02). Overall, these results indicate that NAc DA response to systemic morphine was 
significantly reduced in h/mOPRM1-118GG genotype as compared with h/mOPRM1-118AA genotype. 
Repeated measures ANOVA (genotype – between-factor, dose and time – within-factors) conducted for 
LMA time course data revealed significant main effect of dose (F(3,18) = 62.5; p < 0.001) and dose x genotype 
interaction (F(3,18) = 3.62; p = 0.05). Repeated measures ANOVA (genotype – between-factor, dose – within-
factor) conducted for LMA AUC data also showed significant main effect of dose (F(2,18) = 68.9; p < 0.001) 
and dose x genotype interaction (F(2,18) = 4.5; p = 0.035); however, simple effects of genotype for each dose 
separately were not significant. Overall, these results indicate that systemic morphine administration dose-
dependently increased LMA and these increases were reduced in h/mOPRM1-118GG  genotype as 
compared with h/mOPRM1-118AA genotype.  
 
 


 
 
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Appendix IX.  1SE Inpatient Nursing Information Sheet 
Welcome To 1SE 
Non-Treatment Seeking Participant 
Welcome to 1 Southeast (1SE), a locked behavioral health inpatient research care unit at the 
National Institutes of Health (NIH) Clinical Center in Bethesda, Maryland. Individuals admitted 
to (1SE) take part in clinical research studies with the National Institute on Alcohol Abuse and 
Alcoholism (NIAAA) and the National Institute on Drug Abuse (NIDA). This information has 
been prepared for you to help you adjust to our inpatient research setting. You will also receive a 
general Welcome Book when you are admitted to 1SE to help address any other questions you 
may have concerning your stay with us. Your specific protocol consent form will identify and 
explain what research activities you will be involved in. Thank you for helping to advance our 
understanding of health and illness. 
General Unit Information 
Overview 
 (1SE) is set up as a therapeutic alcohol treatment program. This treatment program is 
approximately a month long and involves many structured activities that are focused on 
alcoholism recovery.  As a non-treatment seeking research participant, you are a guest in this 
community, and will not be participating in the recovery program.  
You will be on 1 SE as an inpatient for a series of short research visits to successfully complete 
your research protocol. Your research procedures and activities are explained in your consent 
form. Beyond your research schedule, you will have time to fill. Please think ahead and bring 
items (for example, personal computers and DVD players) to use this time comfortably. Our 
Recreational Therapy staff may provide some diversional activities. 
You will be accompanied by a member of our research or nursing team at all times while off the 
unit. We provide you with this extra attention to make sure that the research is done the same 
way with each of you. This allows the scientists to compare your results with confidence to that 
of all of the other participants, thus maintaining the integrity of our research protocols.  
Medications from Home 
As part of our safety routines, we ask all research participants to tell us what medications that 
they are taking on admission.  If you bring any of your medication with you, your nurse will 
collect it from you and store it in a secure location until your discharge. While you are an 
inpatient, all of your medications will be dispensed by your nurse, including your own 
medications as well as the study medication(s) which may be part of your research protocol. 
Because of our hospital policy, you will not be allowed to keep any medication in your room.          
Sharps Objects and Toiletries 
Upon admission your personal belongings will be searched. For everyone’s safety, no sharp 
objects such as razors, nail clippers, knives or keys can be kept in your room. Personal care items 
containing alcohol such as after-shave lotions, colognes, and perfumes also will be stored in the 
nurses’ station. You may ask for them when you need them for short-term use, and return them 
to a nurse after each use. Your belongings will be returned to you upon discharge.  
Activity/Privilege Levels 
Because (1 SE) is a locked unit, your ability to leave the unit is dependent on your 
physical/mental status and the requirements of your research protocol. The 1SE privilege levels 
are as follows:  Level 1 – Restricted to Unit, Level 2 – Staff Accompanied while off the unit, 


 
 
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Level 3 – May leave the unit alone in the CRC or on the NIH Grounds. All patients are required 
to sign out and sign back in upon return to the unit.  
Smoking Policy 
NIH is a smoke free campus. However, (1 SE) patients are permitted to smoke if they have a 
Physician’s order, in a restricted area designated only for smoking. Your Nurse will show you 
where this is located should you be interested. Please be aware that your research protocol 
requirements may limit your ability to smoke. 
Food 
For regular meals, you will have a choice of menus. You may eat your meals in your room or at 
the communal tables in the day room area. Visitors may bring food items to you but they must be 
checked by the nursing staff. Please be aware that certain research protocols have dietary 
requirements that impact the type of diet you might be on as well as the times that you may eat. 
This type of specific dietary information is covered in your protocol consent form. Research staff 
will also review this information with you individually. Generally, meals are served at the 
following times: Breakfast: 7:30 AM -8:00 AM, Lunch: 11:30 AM – 12:15 PM, Dinner: 4:45 
PM – 5:15 PM. 
Cell Phones and Laptops 
You may use your cell phone on the unit. However, we ask that you do not talk on your cell 
phone in the day room area where other patients might be involved in treatment or recreational 
activities. Additionally, we ask that you do not bring your cell phone to any research related 
activities. You may use your laptop in your room and in the common areas.  
Rooms 
1SE has two single rooms and six double rooms. The single rooms are generally reserved to 
accommodate patients with specific protocol and/or clinical requirements. Therefore, we cannot 
guarantee that you will be able to have a single room. Each room is equipped with a full 
bathroom, a comfortable bed, dressers and closet space. The staff of 1SE will make every effort 
to maintain your privacy. However, due to unit safety requirements, 1SE nurses make safety 
rounds on patients every 30 minutes during the day and every hour during the night to make sure 
all patients are safe and accounted for. If you have any additional questions or concerns please 
ask your nurse.  
We thank you in advance for your participation and welcome you to our research care unit. With 
24 -hour Nursing care and Research team members available to you; we are working to offer you 
a safe, comfortable and meaningful stay with us.  
 
 
 


 
 
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Appendix X. Plan for clinical monitoring of participants 
receiving morphine at NIDA: 
 
Note:  Equivalent medications and equipment may be substituted with those listed here based on 
need and availability.  This document is a guideline and all numbers provided herein are 
guidelines and must be accompanied by sound clinical judgment when decisions are made. 
 
Equipment/medications to be available: 
 
1. Crash cart with multiple doses of naloxone 
2. 1mg/ml Naloxone hydrochloride injection USP, for intravenous, intramuscular and 
subcutaneous administration 
a. Ten 2 mL single dose disposable prefilled syringes, in the MIN-I-JET® system 
with 21 G. x 11/2” needle. Boxes of 25.  NDC 76329-1469-5, Stock No. 1469 
(contains no preservative), or 
b. Ten 2 mL single dose disposable Luer-JetTM Luer-Lock Prefilled Syringe. Shrink 
Wrapped Packages of 10.  NDC 76329-3369-1, Stock No. 3369 (contains no 
preservative)  
3. Epinephrine IM (EpiPen, Adrenaclick, Twinject, etc.) 
4. Diphenhydramine 25-50mg PO or 10-50mg IV/IM 
5. Ranitidine 150mg PO or 50mg IV/IM 
6. Ondansetron ODT (Orally Disintegrating Tablets) 4mg 
7. Solumederol 8mg PO or prednisone 10mg PO 
8.  Supplemental oxygen tank with tubing 
9. Nasal cannula 
10. Venturi mask 
11. Pulse oximeter 
12. Portable blood pressure/heart rate monitor 
13. Normal saline (3 bags) 
14. Electrocardiogram machine 
Plan: 
1. Personnel with NIH medical credentials (MD, PA, or RN) and ACLS certification as well 
as the investigator administering the tests will be in the room with the participant from 5 
minutes before the injection until 30 minutes after the injection.   
2. Participant’s respiratory rate and oxygen saturation will be continuously monitored by 
pulse oximetry.   
3. If participant’s oxygen saturation level drops below 94% for >1-2 minutes, he will be 
given supplemental oxygen.  If the oxygen saturation level improves, the participant will 
be allowed to continue the study. 


 
 
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4. If participant’s oxygen saturation level drops and remains below 90% for >1-2 minutes or 
his respiration rate drops below 8 breaths/min, or s/he becomes sedated and difficult to 
arouse the following will be done: 
a. Discontinue morphine.   
b. Administer supplemental oxygen by Venturi mask    
c. If no improvement, administer Naloxone 0.2-0.4mg IV/IM/SC .  
Additional Naloxone 0.2-0.4mg IV/IM/SC may be administered every 2-3 
minutes if no response.  Given the short half-life of naloxone (30-90 
mins), naloxone will be repeated if vital signs or participant condition 
indicates re-sedation prior to arrival of emergency personnel.  
1.If participant does not respond to above measures, call 911 and transport 
to the Johns Hopkins bayview Emergency Room  
2.Participant will be disqualified from the study. 
5. If participant vomits or feels excessively nauseous, he will be disqualified from the study. 
 
 


 
 
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Appendix XI. Plan for clinical monitoring of participants 
receiving morphine at the NIH Clinical Center in the Course 
of PET sessions 
Note:  Equivalent medications and equipment may be substituted with those listed here 
based on need and availability.  This document is a guideline and all numbers provided 
herein are guidelines and must be accompanied by sound clinical judgment when decisions 
are made. 
1. Rapid Response Team (ICU staff) receive a courtesy call notifying them in advance of 
the time and location for this study session by the Research Coordinator.  
2. The ACLS certified physician responsible for the participant and drug administration 
has called the RRT and given a brief clinical report and confirmed dosing time. 
3. A full stocked Code Cart remains in the designated area in Interventional Radiology 
(including a suction device), 40 Seconds walking distance from the PetScan room. 
4. A full stocked, ACLS Code Cart Tray provided by Pharmacy will remain in the PetScan 
room for the duration of the session, by the Clinical Nurse manager  
5. Emergency drugs, prepared for immediate administration have been provided to our 
ACLS physician to be held by this M.D. on hand for the duration of the study session, 
including Naloxone, Atropine and Ondansetron. 
6. A bell will be given to the participant once in the PET Scanner with proper 
instructions to use at any point in time during the study session as a means to signal 
distress in addition to free verbal expressions.  
 
7. Code cart with multiple doses of naloxone 
a. 1mg/ml Naloxone hydrochloride injection USP, for intravenous, intramuscular and 
subcutaneous administration.  Initial naloxone dose should be 0.4mg, and 
subsequent doses 0.4-2.0mg. The rationale for starting with the lower dose is to 
avoid precipitating an opioid withdrawal reaction should the subject have a high 
degree of tolerance due to the use of some synthetic opioid that has remained 
undetected by our biochemical tests. 
b. Ten 2 mL single dose disposable prefilled syringes, in the MIN-I-JET® system with 
21 G. x 11/2” needle. Boxes of 25.  NDC 76329-1469-5, Stock No. 1469 (contains no 
preservative), or 
c. Ten 2 mL single dose disposable Luer-JetTM Luer-Lock Prefilled Syringe. Shrink 
Wrapped Packages of 10.  NDC 76329-3369-1, Stock No. 3369 (contains no 
preservative)  
8. Atropine sulphate IV: 1mg/ml 
Dose of 0.5 ml IV push PRN for acute symptomatic bradycardia. This dose may be repeated 
every 3 to 5 minutes up to a maximum total dose of 3 mg 
9. Epinephrine IM: (EpiPen, Adrenaclick, Twinject, etc.) 
10. Diphenhydramine: 25-50mg PO or 10-50mg IV/IM 
11. Ranitidine: 150mg PO or 50mg IV/IM 
12. Ondansetron: 2mg/ml. Dose 4 mg IV push PRN nausea and/or vomiting 
13. Solumederol 8mg PO or prednisone 10mg PO 
14. Supplemental oxygen with tubing, in the PetScan room attached to the wall. 


 
 
CNS IRB Protocol Template (rev 9.21.11) 
 
 
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15. Nasal cannula 
16. Venturi mask 
17. Pulse oximeter 
18. Portable blood pressure/heart rate monitor 
19. Normal saline (3 bags) 
20. Electrocardiogram machine 
Plan: 
1. Personnel with NIH medical credentials (MD, NP, or RN) and ACLS certification as well as the 
investigator administering the tests will be in the room with the participant from 5 minutes 
before the injection until 60 minutes after the injection.   
2. Participant’s respiratory rate, oxygen saturation, heart rate and blood pressure will be 
continuously monitored.   
3. If participant’s oxygen saturation level drops below 94% for >1-2 minutes, he will be given 
supplemental oxygen which will be adjusted to reach a target saturation of 94% or higher.  If 
the oxygen saturation level improves, the participant will be allowed to continue the study. 
4. If participant’s oxygen saturation level drops and remains below 90% for >1-2 minutes or his 
respiration rate drops below 8 breaths/min, or s/he becomes sedated and difficult to arouse 
the following will be done: 
a. Discontinue drug administration if still ongoing, terminate study session, and 
rapidly remove subject from the scanner bed to a position that allows adequate 
observation and access for procedures. 
b. Administer supplemental oxygen by Venturi mask, adjusting it to achieve a 
target saturation of 94%  or higher If no improvement, administer Naloxone 
0.4mg IV/IM/SC  and call the Code team. 
c. Observe for signs of precipitated withdrawal due to use opioid use that has been 
undetected by drug screens. If no signs of withdrawal, additional Naloxone 0.4-
2.0 mg IV/IM/SC may be administered every 2-3 minutes if no response.  Given 
the short half-life of naloxone (30-90 mins), naloxone will be repeated if vital 
signs or participant condition indicates re-sedation prior to arrival of emergency 
personnel.  
5. If participant displays clinically significant bradycardia, hypotension or a clinically 
significant combination thereof, Initiation of the standard ACLS algorithm and  the Code 
team will be called for treatment of these conditions, i.e. atropine 0.5mg IV push, may repeat 
up to a total dose of 3mg. If there is not an adequate response to this intervention, consider 
initiating the next step of the standard ACLS algorithm, i.e. administration of epinephrine, 
and initiating IV fluid.  
6. If participant displays any of the problems above, vomits or feels excessively nauseous, or 
displays any other adverse reactions such as e.g. excessive sedation, anxiety or allergic 
symptoms and these cannot be adequately managed, (the subject will be removed from the 
scanner [note: Clinical Center version]) any ongoing research procedures will be 
discontinued, and subject will be placed in a position that ensures free airways, adequate 
observation, and access for procedures. 
Revised 3/20/2014