Clinical trial NCT02360371
Conditions: Opioid Sensitivity Individual Difference Abuse Opioids
Keywords: opioid abuse genetic A118G OPRM1
Sponsor: Johns Hopkins University
Start date: 2015-04-01; Completion date: 2021-05-01
Enrollment: 100 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Within-subject, double-blind, placebo-controlled examination of opioid abuse potential in healthy individuals as a function of A118G SNP on the OPRM1 gene.

Detailed description:
Participants completed a 5-day, within-subject, double-blind, placebo-controlled, randomized, human laboratory abuse potential trial. Healthy individuals were admitted to a residential research unit for 5 consecutive days. Blood samples were drawn for genome wide analyses using the Global Screening Array on day 1. Participants were administered an oral dose of the opioid hydromorphone (4mg) on day 2 of the study. Persons who did not evidence strong agonist effects then proceeded into the randomized period wherein they received 0mg, 2mg, and 8mg of oral hydromorphone on the remaining three study days. The order of dosing was randomized, with only 1 dose administered per day and all participants receiving 1 exposure to each dose. Outcomes were standard human abuse potential metrics, including self-reported drug effects and feeling high. Data were analyzed as a function of the A118SNP on the OPRM1 gene that codes for the mu opioid receptor. The overall aim was to determine whether signal for abuse potential among persons with no history of opioid misuse was associated with genotype.

Arms: arm 1: Within-subject double-blind, administration of placebo oral capsule. Order of dose randomized session days 3-5. arm 2: Within-subject double-blind, administration of hydromorphone via oral capsule. Order of dose randomized session days 3-5. arm 3: Hydromorphone oral capsule administered in double-blind manner on Day 2 as first study drug administration. Hydromorphone 4mg dosing day was set for safety purposes and non-randomized. arm 4: Within-subject double-blind, administration of hydromorphone via oral capsule. Order of dose randomized session days 3-5.
Interventions: intervention 1: Within-subject test of blinded study medication
Intervention descriptions: intervention 1: Within-subject double-blind, randomized, placebo-controlled, residential human abuse potential study. All participants received 4mg oral hydromorphone on study day 2 and a subset continued into the randomized portion for study days 3-5 wherein they received placebo, 2mg hydromorphone, and 8mg hydromorphone in randomized order. Only one dose was administered per day and following randomized all participants received each dose in random order. Outcomes were collected during 8-hour residential-based sessions and included metrics of FDA human abuse potential testing as well as secondary outcomes of laboratory pain testing, subjective reports of drug effects, and cognitive performance, evaluated as a function of study medication condition. Participants were genotyped for rs-1799971 status and results were analyzed as between-group comparisons based upon genotype.

Protocol documents:
Prot_SAP_000.pdf: 
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NCT: 02360371 
 
Title: A118G SNP and OPRM1 Gene Opioid-mediated Effects in 
Humans 
 
PI: Kelly Dunn, Ph.D., MBA 
 
Document Date: October 16, 2019 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Date: October 16, 2019 
Principal Investigator: Kelly Dunn, Ph.D. 
Application Number: IRB00047423 
 
 
 
JHM IRB - eForm A – Protocol 
 
 
 Use the section headings to write the JHM IRB eForm A, inserting the appropriate material in each. If 
a section is not applicable, leave heading in and insert N/A. 
 When submitting JHM IRB eForm A (new or revised), enter the date submitted to the field at the top 
of JHM IRB eForm A. 
 
********************************************************************************************** 
 
1. 
Abstract 
a. Provide no more than a one page research abstract briefly stating the problem, the research hypothesis, 
and the importance of the research. 
Abuse of opioids is a significant national health problem. Pharmacogenetics, or personalized medicine, uses genotype 
information to predict phenotypic response (generally medication efficacy or safety). The field of substance abuse is 
critically lagging behind in the application of pharmacogenetics for identifying individuals at increased risk for 
developing an opioid abuse disorder, or using personal genetic information to guide treatment. There is growing 
evidence to suggest a functional polymorphism (A118G) in the OPRM1 gene that codes for the mu opioid receptor 
(MOR) mediates individual response to opioid medications and has direct relevance for the development of opioid 
dependence. To date, no controlled human laboratory studies have examined the effect of the A118G SNP or 
OPRM1 gene on individual response to opioids. The next logical step is to evaluate whether differences in OPRM1 
single nucleotide polymorphisms (SNPs) drive individual response to opioid medications, which will help advance 
the field of substance abuse towards a pharmacogenetics approach to treatment, and establish a precedent for using 
controlled and well-validated laboratory methodology to investigate the genotype-phenotype interactions of opioids. 
We are proposing to conduct a laboratory study to evaluate whether the A118G SNP and additional OPRM1 tagging 
SNPs are associated with a variety of different MOR-mediated functions by evaluating subjective and physiological 
response to double-blind administration of an opioid medication. We will also evaluate the contribution of OPRM1 
on other complex phenotypes related to the MOR activity or opioid dependence (e.g., pain sensitivity, the 
endogenous opioid-mediated cortisol stress response, and a delay discounting behavioral economic task). This study 
will be a between-group evaluation of genotype and sex, and a within-subject evaluation of opioid dose-response that 
will be conducted over 5 days in a residential clinical research unit. Study completers (n=100) will receive double- 
blind doses of oral hydromorphone or placebo in a randomized, counter-balanced research design. Self-report, 
physiological, and salivary cortisol measures of drug effects will be collected at several time points following drug 
administration, and delay discounting will be administered at screening and during peak drug effects. We will also 
administer different operant pain tasks that provide quantifiable estimates of pain sensitivity, under conditions of 
placebo or hydromorphone administration. This study will be the most controlled, rigorous, comprehensive 
examination of the A118G SNP and OPRM1 gene with opioid-mediated effects to date. We expect that genotype will 
be associated with several opioid-mediated effects, and that the results will advance our understanding of the 
contribution of OPRM1 to specific behavioral phenotypes. These data will advance the use of pharmacogenetics for 
substance abuse and use of laboratory testing for genotype-based hypotheses, and will contribute to the development 
of opioid dependence prevention strategies and interventions to treat comorbid pain and opioid dependence. 
 
2. 
Objectives (include all primary and secondary objectives). 
The primary aim of this study is to examine the associations of specific polymorphisms in the OPRM1 gene with 
mu opioid receptor (MOR)-mediated effects. We hypothesize the minor A118G SNP allele and OPRM1 tagging 
SNPs will predict more reinforcing properties of hydromorphone, (e.g., higher self-report ratings of high and drug- 
liking) and greater opioid-induced physiological changes (e.g., pupil diameter, blood pressure), decreases in cortisol 
levels as a function of the degree of pleasant effects of hydromorphone, and steeper discounting curves on a delay- 
discounting task. The secondary aim of this study is to examine the associations of specific polymorphisms in the 
OPRM1 gene with laboratory measures of pain. We hypothesize the minor A118G SNP allele and OPRM1 tagging 


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SNPs will predict higher pain threshold on two experimentally-induced laboratory measures of pain, lower analgesic 
efficacy in response to experimentally-induced pain, and lower cortisol response to painful stimuli. Finally, as an 
exploratory aim, we will examine the contribution of sex to the primary and secondary aims. 
 
3. 
Background (briefly describe pre-clinical and clinical data, current experience with procedures, drug or 
device, and any other relevant information to justify the research) 
 
Abuse of opioids has resulted in a 57% and 717% increase in treatment admissions between 1992-2008 for 
heroin and prescription opioids, respectively (1). Opioid dependence is a chronic, relapsing disorder that is associated 
with greater health care services, more emergency room visits, prolonged disability, missed work days, and frequent 
overdose, resulting in an annual societal cost of more than $8 billion (8 fold greater than nonabusers; (2, 3). 
Laboratory evaluations of opioids medications reveal robust and consistent between-person differences in self-report 
and physiological response to opioids (4-8), however no persistent demographic, drug use, and/or treatment 
characteristics have been identified that reliably predict susceptiblity to develop opioid dependence (9-15). The 
phenomenon of varied individual response to drugs is not limited to opioid medications and clinically causes 
reductions in efficacy of medications and increased side effect profiles (16, 17). Pharmacogenetics, one approach to 
personalized medicine, addresses this phenomenon by using genotype information to predict phenotypic response 
(generally medication efficacy or safety; (18, 19). Regarding opioids, there is growing evidence to suggest a 
functional polymorphism in the OPRM1 gene that codes for the mu opioid receptor (MOR) may mediate individual 
response to opioid medications and have direct relevance for the development of opioid dependence (20-25). The 
most commonly researched single nucleotide polymorphism (SNP) of the MOR is a nucleotide exchange in exon 1 at 
the 118 position of the N-terminal domain (26), which results in an amino acid change from aspargine to asparate at 
position 118 (Asn40Asp or A118G, rs1799971). 
We were the first group to show that the A118G SNP of the OPRM1 gene has functional consequences on 
human behavior (27). Human laboratory studies have reported a reliable and robust, endogenously-mediated cortisol 
response to the opioid antagonist naloxone (27-32), a greater adrenocorticotropic hormone stress response (29), and 
decreased pupillary constriction (33-35) in response to opioid administration. Laboratory studies examining alcohol 
and nicotine have reported functional associations between the A118G SNP of the OPRM1 and behavioral outcomes 
such as increases in striatal dopamine following nicotine exposure (36), decreased cerebral blood flow following 
nicotine abstinence (37), increased MOR binding potential (38) and MOR availability (39), finding smoking more 
reinforcing (40, 41), and greater sensitivity to alcohol. Most recently we have identified that the minor allele predicts 
lower D2/D3 receptor binding potential in the nucleus accumbens (Wand and co-workers, editorial review in 
preparation). Altogether, these data are now being used to predict clinical differences in treatment response based on 
OPRM1 status, such as efficacy of naltrexone for alcohol treatment (42, 43), nicotine replacement products for 
nicotine (44, 45), and severity of nicotine withdrawal symptoms (46). The field of medicine has embraced the 
promise of pharmacogenetics more broadly and has published several studies that use genotype to guide treatment for 
alcohol (47), breast cancer (48), hepatitis C (49), warfarin (see (50), leukemia (51), AIDS (52), P450 enzymes (53), 
psychotropic medications (54), and pain (55). This approach has great potential because it prevents physicians from 
prescribing medications that have a lower likelihood of working or are unsafe within different genetic subgroups, 
ultimately increasing efficiency, reducing time to positive therapeutic response, and minimizing potential side effects 
of medications. Patients also support the use of genetics to guide prescribing (56). 
The field of substance abuse is critically lagging behind in the application of pharmacogenetics for 
identifying individuals at increased risk for developing an opioid abuse disorder, as well as using personal genetic 
information for tailoring treatment decisions. The majority of studies that have evaluated the contribution of the 
OPRM1 gene to human behavior are either Genome Wide Association Studies (GWAS) that provided self-report 
surveys to large patient samples and looked for associations, or retrospective chart reviews that collected genetic 
information from clinical patient populations who received opioid medications for pain (21, 57-66). The primary 
pitfalls of these approaches are that the phenotype (e.g., substance abuse) is either poorly defined or unreliably 
measured. The field of genetics has begun moving away from these association models; they do not yield consistent 
results because the measures used to define the phenotype are very heterogeneous across studies and are ultimately 
poor representations of the target phenotypes. Two independent reviews have recently argued that controlled 
laboratory examinations of endophenotypes that are evaluated under rigorous experimental conditions better 
approximate the complex phenotype of drug dependence and produce stronger effect sizes than large-scale 
association studies that rely on retrospective self-report (67, 68). 
To date, no controlled human laboratory studies have examined the effect of the A118G SNP or the larger 
OPRM1 gene on individual response to opioids. The proposed laboratory study is a necessary first step to evaluate 


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whether differences in OPRM1 single nucleotide polymorphisms (SNPs) drive individual response to opioid 
medications, which will help advance the field of substance abuse towards a pharmacogenetics approach to 
treatment, and establish a precedent for using controlled, reliable, and well-validated laboratory methodology to 
investigate the genotype-phenotype interactions of opioids. Laboratory studies are ideal for targeting specific 
behavioral phenotypes because they are rigorously controlled, permit within-subject evaluations of drug effects and 
double-blind dose administration, identify dose-graded effects, target well-established and specific phenotypes of 
drug use behavior that can be directly compared to existing literature to guide interpretation of effects, permit cross- 
laboratory and cross-species comparisons and replication of effects, are robust and reliable predictors of clinical 
outcomes, and produce larger effect sizes than GWAS studies (67, 68). Our group has specific expertise in 
conducting laboratory assessments of opioid effects using a model that is considered the standard by the Food and 
Drug Administration, industry, and national organizations (69). Thus, we are proposing to conduct a laboratory 
study to evaluate whether the A118G SNP and additional OPRM1 tagging SNPs are associated with a variety of 
different MOR-mediated functions by evaluating subjective and physiological response to double-blind 
administration of an opioid medication, pain sensitivity and response to medications for pain (secondary aim, 
beginning Page 9), the endogenous opioid-mediated cortisol stress response, and a delay discounting behavioral 
economic task that has been reliably associated with the drug abusing phenotype. This study will advance our 
understanding of the contribution of genotype to abuse liability, pain, endogenous stress response, and delay 
discounting. These data can be used to modify analgesic doses and treatments, reduce potential for side effects from 
opioid medications, predict susceptibility to opioid dependence (70, 71) and develop innovative intervention 
strategies, and advance the use of controlled laboratory testing to evaluate genotype-based hypotheses. This study 
will also provide a unique opportunity to identify whether these effects are evident among people that demonstrate 
increased abuse potential for opioids prior to the development of opioid dependence. 
There is also substantial individual variation in the subjective response to nociceptive (e.g., painful) stimuli. 
Genetic factors have been shown to contribute to that variation (72-75) and growing evidence indicates the 
functional action of the OPRM1 may influence the associated endogenous opioid response (mediated by beta- 
endorphin) to pain (26, 76). Several studies report that the minor allele of the A118G may confer a resistance to 
nociceptive (e.g., painful) stimuli. First, carriers of the minor allele have lower beta-endorphin-mediated serum 
concentrations of circulating proinflammatory cytokines (77), and a robust beta-endorphin mediated increase in 
cortisol release following naloxone administration (27-32). Second, controlled human experimental studies report 
higher pain thresholds in minor allele carriers (78-81), and a longitudinal cohort study reported higher positive affect 
across 30 days of repeated measurement among A118G minor allele variants with the chronic pain disorder 
fibromyalgia (82), which is consistent with preclinical studies that reported increased pain sensitivity following 
direct administration of beta-endorphin  (83, 84). The minor allele of the A118G has also been consistently 
associated with increased medication requirements to achieve analgesia. For example, preclinical and human 
laboratory studies report that A118G minor allele carriers experience less relief from opioid agonists (85-87), and 
several retrospective chart reviews report greater postoperative medication requirements (35, 88-96). 
Additional, well-controlled studies are needed to understand and advance our knowledge regarding the effect 
of the A118G SNP and additional OPRM1 tagging SNP variants on baseline pain tolerance, and pain tolerance 
under conditions of opioid analgesic treatment. Only two studies have examined the contribution of the A118G on 
pain tolerance in controlled laboratory settings (78, 81). The first study reported positive associations between 
A118G and pain on two of the three pain tolerance tests conducted, but did not evaluate tolerance to pain following 
opioid agonist administration (78, 81). The second study reported a positive association with OPRM1 on one test of 
pain following oxycodone administration, but did not evaluate additional pain tolerance tests, which is important 
given the high rate of individual variability among pain testing methods (78, 81). Neither study sampled across the 
OPRM1 gene and or was designed to prospectively evaluate gender, which is critical because of the robust gender- 
specific effect that exists on pain and its potential interaction with the OPRM1 gene (41). The current study will 
extend upon these studies by evaluating the effect of the A118G SNP and OPRM1 gene using a quantitative sensory 
testing (QST) paradigm, under conditions of double-blind and placebo-controlled hydromorphone administration, 
and will conduct gender specific analyses. Women will only be enrolled during the first two weeks of their cycle 
(confirmed via progesterone analysis) to minimize hormonal effects on pain, which will be the most rigorous 
evaluation of OPRM1 and pain within gender to date. Further, one of our pain tests will activate the diffuse noxious 
inhibitory control (DNIC) system, which is mediated by the endogenous opioid system, hypothesized to be a model 
of chronic pain, and believed to contribute to opioid-induced hyperalgesia (97). No prior study has used the DNIC 
procedure to evaluate OPRM1 effects on pain tolerance, which is critical because of the established functional 
relationship between the OPRM1 and the endogenous opioid response (26, 98). The results will advance our 
understanding of the OPRM1 contribution to pain tolerance and response to medication, help elucidate the 


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mechanism behind opioid-induced hyperalgesia, and may be used clinically to guide development of chronic pain 
interventions and prescribing guidelines. These results will also be compared to abuse liability outcomes, which- to 
our knowledge- will be the first within-person comparison of opioid abuse liability and pain effects as a function of 
genotype. 
 
4. 
Study Procedures 
a. Study design, including the sequence and timing of study procedures 
(distinguish research procedures from those that are part of routine care). 
 
Study Overview: This study will be a between-group (total completer N=100) evaluation of genotype and sex, and a 
within-subject evaluation of opioid dose-response. The study will be conducted over 5 days (4 nights) at the 
Behavioral Pharmacology Research Unit (BPRU) and a residential clinical research unit (CRU) (Figure 1). Day 1 
will be an Admission day. Days 2-5 will consist of blinded study drug administration in the morning, 1 pain testing 
session, and self-report/physiological measures of drug effects for 6 hours post dosing. Participants will receive 
double-blind doses of oral hydromorphone (2mg, 4mg, 8mg) (99-102) or weight and color-matched placebo in a 
randomized, counter-balanced research design. 
 
Screening Visit: Participants will complete a brief phone screen to determine initial eligibility and will be invited to 
complete an in-clinic screen. Participants will sign an informed consent form with a study staff member to begin the 
Screening visit. To reduce expectancy effects, the consent will inform participants the study drug may consist of one 
or more of numerous different drug classes (e.g., opioids, stimulants, over-the-counter medications), a common 
practice in laboratory based studies of drug effects (103, 104). Following consent, a staff member will administer a 
battery of measures to establish study eligibility (see Study Measures below). A urine sample will be collected and 
tested for evidence of illicit drugs and to establish medical eligibility. A blood sample of no more than 2 tablespoons 
will also be collected from eligible participants for medical and genotype analysis. Participants will also be asked to 
provide a second blood sample (2 additional tablespoons) that will be collected at either Screening or Admission and 
stored for future genetic analysis. This will be voluntary. Participants who meet eligibility criteria (including results 
of laboratory blood tests) will be scheduled for an Admission day. 
 
Study Day 1, Admission Visit: Participants will complete a brief history and physical to determine final study 
eligibility and will be admitted to the CRU for 5 days (Admission day + 4 session days). During the Admission day, 
participants will be familiarized with the pain testing procedures and the measures used during session days 2-5. 
 
Study Days 2-5, Session Days: The morning of each session, participants will be provided with a standardized 
breakfast, and cigarette smokers will be permitted 1 cigarette the morning prior to a session (1 additional cigarette 
will be permitted every 2 hours during the session). Sessions may take place either at the CRU or the BPRU, 
however all participants will reside overnight in the CRU. Participants will receive a standardized lunch and dinner. 
Beginning on Day 2, participants will receive a blinded study drug in the morning, will conduct a pain testing session 
approximately 60-90 minutes post-dose, and will provide self-report, observer-ratings, and physiological measures of 
drug effects for an additional 6-hours post-dosing. Each element is described in more detail below. Participants will 
also provide a blood sample (no more than 1 tablespoon) that will be analyzed for metabolic status. This sample can 
be collected at any point during Study Days 2-5. 
Pain Testing: Participants will undergo 1 pain-testing session each day. Sessions will consist of pressure 
pain threshold, conditioned pain modulation, and temporal summation testing. Participants will be oriented to the 
study measures and pain testing apparatuses during the Admission Day. During the sessions, study drug will be 
administered under double-blind conditions in the morning. Salivary cortisol samples will be collected following 
completion of the pain testing session to evaluate the acute stress response to each pain stimulus, as a function of 
Tuesday 
Wednesday 
Thursday 
Friday 
Placebo, 
Low or 
High Dose 
Monday 
 
 
 
 
 
Eligibility 
Assessment 
Placebo, 
Low or 
High Dose 
Placebo, 
Low or 
High Dose 
Daily Sessions: Self-report, observer ratings of 
drug effects, QST pain testing during peak effects, 
delay discounting, salivary cortisol collection 
Mid Level 
Dose 
Admission 
to CRU 
 
Screening 
Timeline of Study Events 


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drug (placebo vs. hydromorphone). Ratings of numeric rating scales will be used for data analysis, and participants 
will be asked to identify whether a placebo or active drug had been administered. 
Pressure Pain Threshold: The pressure pain threshold is defined as the kilopascals (kPA) value at which a 
mechanical stimulus is first judged to be painful. An electronic algometer with a 1cm2 hard rubber probe will be 
applied two times to two different muscle groups in randomized order. Pressure will be applied at a constant rate of 
30kPA/s until the participant first reports pain. A 30 second interval will be imposed between each stimulus 
presentation (105). The values in kPA will be averaged across administrations and muscle groups to create an index 
of pressure pain threshold. Administering the stimulus at multiple anatomic locations increases the reliability of the 
pressure pain threshold. Possible effects of laterality and muscle group will be evaluated to determine if threshold 
outcome measures should be separated into subgroups. 
Conditioned Pain Modulation: We will also conduct a test of conditioned pain modulation, 
formerly known as diffuse noxious inhibitory controls. Conditioned pain modulation is the process by which the pain 
induced by a tonic conditioning stimulus inhibits the pain produced by another noxious stimulus at a distal anatomic 
location. This procedure initiates a robust activation of the endogenous opioid system that is attenuable by 
administration of naltrexone (106). Our conditioned pain modulation procedure will measure the change in pressure 
pain threshold at the trapezius muscle induced by immersion of the contralateral hand in cold water. Two baseline 
pressure pain threshold readings will be assessed via algometry. Participants will then immerse their hand in a 
circulating ice water bath maintained at 10 +/- 1¡ C and will not be told the duration of time for which their hand will 
be submerged. After 20 seconds, with their hand still submerged, participants will rate their pain on a 0-100 numeric 
rating scale (NRS; (107), where 0=No Pain and 100=is Worst Pain Imaginable, and after 45 seconds participants will 
be asked to remove their hand from the water bath. Simultaneously with hand withdrawal, an algometer will be 
applied and pressure pain threshold in kPA will be recorded. This procedure will be repeated contralaterally after a 5- 
minute interval. The order of administration with respect to laterality will be randomized. Conditioned pain 
modulation will be indexed as the percent change in pressure pain threshold from the baseline administration to the 
conditioned administration, averaged across the 2 trials (105). Conditioned pain modulation can be conducted with a 
variety of heterotopic conditioning stimuli, including thermal, ischemic, and electrical stimuli. Cold-water immersion 
(also known as the cold pressor test) is an attractive choice for the conditioning stimulus because noxious cold 
stimuli activate cutaneous A∂ and C fibers, resulting in rapid nociceptive neurotransmission (108). This conditioned 
pain modulation method has been selected for this study because it has been independently validated as a sensitive 
and reliable measure of descending pain inhibition (109), and it activates the endogenous system that is hypothesized 
to be altered by the OPRM1 gene. 
Mechanical Temporal Summation. Temporal summation of pain will be assessed using repetitive mechanical 
stimuli. The assessment of temporal summation involves rapidly applying a series of identical noxious stimuli and 
determining the increase in pain across trials; animal studies have suggested that temporal summation occurs 
centrally in second-order neurons in the spinal cord as a consequence of sustained C-fiber afferent input (149-151). 
For temporal summation of mechanical pain, pain ratings in response to a single punctate noxious stimulus will be 
compared to pain ratings in response to a sequence of identical punctate noxious stimuli (152). A weighted pinprick 
stimulator with a flat contact area will be used to deliver either a single pinprick stimulus or a train of 10 pinprick 
stimuli repeated at a constant rate. Following the single stimulus and the 10-stimulus train, the subject is asked to 
give a pain rating. Single pinprick stimuli are alternated with the trains of 10 stimuli. Similar procedures using this 
type of weighted pinprick stimulator have been used in diabetic neuropathy (153), healthy subjects (154), and to 
assess temporal summation (155-156). 
 
Acute Effects of Hydromorphone: Participants will ingest medication under staff supervision and complete 
a battery of self-report, physiological, and cortisol measures will be collected prior to dosing and up to 15 time points 
post-dose (up to 6 hours). During the final assessment each day, participants will complete a Drug vs. Money 
Questionnaire modeled from the Multiple Choice Procedure to indicate the dollar value they would place upon the 
drug received and this measure will be repeated immediately prior to the next day’s drug administration. These 
experimental procedures are consistent with those used in a previous study by our group (110). Participants will be 
discharged from the study on the final day after completing the final study assessment and a field sobriety test that 
indicates no persistent opioid effects. We will conduct a follow-up phone call with participants the day following 
discharge to document any adverse events and to administer the final Drug vs. Money Questionnaire. 
 
General Study Assessments: We have included several measures during the Screening visit to enable us to 
characterize the population and collect preliminary information that might differentiate between genetic groups or be 
used to support future research applications, including a questionnaire to evaluate domains the NIDA Genetic 


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Council recommends be documented in genetic studies. The measures comprise both pharmacologically and 
qualitatively nonspecific measures (e.g., any drug effect) and qualitatively specific measures (e.g., liking, good 
effects, bad effects, nausea), which have been recently recommended by a consensus panel and the FDA. OPRM1 
has recently been associated with negative side effects of opioid medications so we will specifically assess negative 
symptoms and side effects following drug administration. 
 
Study Measures to Establish Eligibility and Characterize Sample: 
 BPRU Demographic Questionnaire: A questionnaire designed by us to document standardized demographic 
items (e.g., age, gender, marital status). 
 Alcohol/Drug subscale of the Addiction Severity Index (111): A 31-question subscale that assess past 30 day 
and life-time use of drugs, history of treatment, and interest in treatment. Subscales provide a measure of 
severity. 
 MINI International Neuropsychiatric Instrument: A standardized semi-structured diagnostic interview assesses 
participants for evidence of psychiatric disorders. The MINI will be used to verify that participants do not meet 
DSM-IV-TR dependence on alcohol and/or drugs. 
 NIDA Genetic Questionnaire: This questionnaire lists several specific questions recommended by the NIDA 
Genetic Council for any study conducting research on the pharmacogenetics of substance abuse. 
 Brief Pain Inventory (BPI; (112)): A 9-item widely-used, standardized, self-report measure to characterize the 
presence and severity of pain, as well as the interference of pain in every-day activities. The BPI has been 
modified to be appropriate for self-administration, and for use in an opioid-treatment population. 
 Fagerström Test for Nicotine Dependence (FTND; (113)): A 6-item measure to determine presence of smoking 
and severity of nicotine dependence. 
 Profile of Mood States-2 (114): A 65-item questionnaire that is a standardized and normed measure of 
personality that yields a measures of different personality features (anger-hostility, confusion, depression, 
fatigue, tension-anxiety, vigor, and friendliness). 
 Barratt Impulsiveness Scale (115): A 30-item, widely used measure of impulsivity that will provide a self-report 
comparison to the delay discounting test of impulsivity. 
 The Positive and Negative Effect Scale (PANAS; (116)): A 20-item self-report measure to characterize positive 
and negative emotional responses to pain. 
 Coping Strategies Questionnaire- Short Form (CSQ Short Form; (117)): A 16-item self-report measure to 
characterize emotional response to pain and perceived efficacy of coping strategies. 
 Pain Catastrophizing Scale (PCS; (118)): A 14-item self-report measure to characterize the emotional response 
to pain, with particular emphasis on anxiety and/or fear of pain. 
 McGill Pain Questionnaire-Short Form (MPQ Short Form; (119)): A 15-item widely-used standardized, self- 
report measure to characterize presence and severity of pain. 
 
Session Measures: 
 Clinical Opiate Withdrawal Scale (120): A widely used, 11-item observer-rating of opioid withdrawal 
symptoms. 
 Vital Signs: We will assess blood pressure, pulse, respiration, and oxygen saturation. 
 Pupillary Diameter: Pupil size will be assessed using an electronic Neuroptics Pupilometer 
 Visual Analog Rating Scales: Participants will rate the following items on a scale of 0 (none at all) to 100 
(strongest possible): good effects, bad effects, high, withdrawal, sick, like how I feel, nausea, sedation, feel 
sleepy 
 Opioid Agonist/Antagonist Rating Scale: This questionnaire assesses positive and negative effects of opioids. 
 Drug vs. Money Questionnaire: This questionnaire is a frequently used measure to assess relative monetary value 
of a drug and is being used to assess relative reinforcing effects of the drug compared to hypothetical monetary 
values. 
 Neurocognitive Assessment: A battery of tasks designed to measure neurocognitive performance that has been 
developed by our research unit will be adapted for this study. Functions to be tested include psychomotor 
speed/pattern recognition (e.g. digit symbol substitution) and short-term/working memory and focused attention 
(e.g. N-back task). 
 Hypothetical Purchase Task: This questionnaire is used to measure the abuse liability of drugs by assessing the 
magnitude and persistence of demand for a given drug under cost constraints. Participants indicate how many 
drug units (i.e., capsules) they would purchase at increasing price points for a 24-hour period of use. 


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Delay Discounting (DD): 
 We will administer monetary and commodity-based DD tasks via computer to participants during the Screening 
visit, and each session day during peak drug effects (30 minutes). DD for $100 will be assessed using a computer 
program developed by Co-investigator Johnson that has been utilized in numerous studies (121-126) and will be 
quantified using the area-under-the-curve (AUC) method (127). The hypothesized results are that the minor 
allele of the A118G and other minor alleles of OPRM1 tagging SNPs will be associated with steeper discounting 
curves (less AUC). 
 
Genetic Analysis: Genotyping will be supervised by Co-Investigator Wand. All blood genetic samples will be 
collected and transported to the main Hopkins hospital on a weekly basis for analysis. A chain of custody will be 
kept to ensure proper delivery and receipt of all samples. No participants name will be written on any genetic sample 
and participants will not be informed of the results of the genetic testing. 
For all SNPs across the OPRM1 gene including the A118G and ancestral markers (see Statistical Analysis), 
genotyping will be performed with GoldenGate Genotyping Assay. The DNA sample used in this assay is activated 
for binding to paramagnetic particles. This activation step is a highly robust process that requires a minimum input of 
DNA (250ng at 50ng/µl). Depending upon the multiplex level, this equates to only 160pg of DNA per SNP genotype 
call. Assay oligonucleotides, hybridization buffer, and paramagnetic particles are then combined with the activated 
DNA in the hybridization. Three oligonucleotides are designed for each SNP locus. Two oligos are specific to each 
allele of the SNP site, called the Allele-Specific Oligos (ASOs). A third oligo that hybridizes several bases 
downstream from the SNP site is the Locus-Specific Oligo (LSO). All three oligonucleotide sequences contain 
regions of genomic complementarity and universal PCR primer sites; the LSO also contains a unique address 
sequence that targets a particular bead type. Up to 1,536 SNPs may be interrogated simultaneously in this manner 
using GoldenGate technology. During the primer hybridization process, the assay oligonucleotides hybridize to the 
genomic DNA sample bound to paramagnetic particles. Because hybridization occurs prior to any amplification 
steps, no amplification bias can be introduced into the assay. Following hybridization, several wash steps are 
performed, reducing noise by removing excess and mis-hybridized oligonucleotides. Extension of the appropriate 
ASO and ligation of the extended product to the LSO joins information about the genotype present at the SNP site to 
the address sequence on the LSO.  These joined, full-length products provide a template for PCR using universal 
PCR primers. Universal PCR primers P1 and P2 are Cy3- and Cy5-labeled. After downstream-processing 5 the 
single-stranded, dye-labeled DNAs are hybridized to their complement bead type through their unique address 
sequences. Hybridization of the GoldenGate Assay products onto the Array Matrix or BeadChip allows for the 
separation of the assay products in solution, onto a solid surface for individual SNP genotype readout. After 
hybridization, the BeadArray Reader is used to analyze fluorescence signal on the Sentrix Array Matrix or BeadChip, 
which is in turn analyzed using software for automated genotype clustering and calling. 
 
b. Study duration and number of study visits required of research participants. 
 
Participants will complete a Screening visit and will be enrolled in this study for a total of 5 days (Admission Day + 
4 session days; Figure 1). 
 
c. Blinding, including justification for blinding or not blinding the trial, if applicable. 
 
Participants will be informed in the consent will that the study drug may consist of one or more of numerous different 
drug classes (e.g., opioids, stimulants, over-the-counter medications). This is a common practice in laboratory-based 
studies of drug effects, a practice that we have followed for several years, and one that is recommended in peer- 
reviewed guidelines for abuse liability testing (103, 104). We will inform participants of the risks associated with 
hydromorphone (without revealing the drug type) in the consent form so they will be able to make an informed 
decision about study participation. Participants will receive double-blind oral doses of hydromorphone or placebo 
during the study to prevent expectancy effects and enable a rigorous evaluation of opioid administration on a variety 
of clinically-relevant outcome measures. Staff members will also be blinded to what study drug is being provided. 
 
d. Justification of why participants will not receive routine care or will have current therapy stopped. 
N/A 
 
e. Justification for inclusion of a placebo or non-treatment group. 


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A placebo condition has been included as a comparison for opioid-induced effects. 
 
f. Definition of treatment failure or participant removal criteria. 
 
Participants will be removed from study participation if they ask to be removed, if they exhibit an allergic reaction to 
the study drug, if they fail to comply with the requirements of the study, or if new information becomes available that 
suggests that continued study participation may put them at increased risk of adverse events. 
 
g. Description of what happens to participants receiving therapy when study ends or if a participant’s 
participation in the study ends prematurely. 
 
Participants are healthy controls. They are not treatment-seeking and do not have any underlying medical condition 
that would warrant continued treatment upon completing the study. Participants will be informed they can agree to 
begin the study now and withdraw later without any penalty. Participants who request to discharge from the study 
prior to completing the study will be assisted with contacting medical professionals upon request from the 
participant. 
 
5. 
Inclusion/Exclusion Criteria 
 
We will recruit healthy volunteers who may have consumed prescription opioids in the past either recreationally or 
for medical purposes, but are not currently dependent (Table 1). Restricting our sample to completely opiate naïve 
individuals would not be feasible, because verifying a history of no opiate use may not be possible, and because we 
did not want to exclude participants who received clinically-indicated prescriptions. Non-dependent drug using 
participants have been strategically chosen to minimize potential confounds with current opioid dependence (e.g., 
tolerance, presence of pain) and human subject concerns regarding need for treatment. Use of non-dependent 
participants is a common practice in laboratory studies of drug effects and there is no evidence to suggest this 
exposure puts individuals at risk for developing drug dependence (see Human Subjects section). Finally, females 
will be enrolled in the study during the 1st two weeks of their menstrual cycle (confirmed via diary and 
progesterone) to control for hormonal influence on opioid effects and pain. We will not exclude females taking 
birth control but may include birth control as a covariate in the statistical analyses. 
 
Table 1. Study Eligibility Criteria 
Inclusion 
Exclusion 
1. Provide a urine sample that tests negative for 
1. Answer “yes” to question 1 of the Brief Pain Inventory (89) to assess the presence 
opioids, methadone, buprenorphine, oxycodone, 
of chronic pain. 
amphetamine, cocaine, and benzodiazepines 
2. Negative ethanol breath test (0.000) 
2. Current use of opioids or other medications for pain 
3. Aged 21-50 
3. Meet DSM-5 criteria for current or lifetime alcohol or drug use disorder (excluding 
nicotine) 
4. Deemed medically eligible to take hydromorphone 
4. Self-report any illicit drug use in the past 7 days 
5. Self-report opioid use >5 days in the past 30 
6. Evidence of opioid physical dependence at screening or following 1st night in CRU 
(following confirmed opioid abstinence) 
7. Allergy to hydromorphone or other opioid agonists 
8. Experience an adverse event that warrants opioid antagonist treatment following 1st 
hydromorphone dose. 
9. If female, not be pregnant or breastfeeding 
10. Presence of any clinically significant medical (e.g., chronic renal insufficiency, 
history of myocardial infarction, seizure disorder) and/or psychiatric illness (e.g., 
schizophrenia, bipolar disorder) that may interfere with study participation. 
11. BMI >30 (obese category) 
 
 
6. 
Drugs/ Substances/ Devices 
 
a. The rationale for choosing the drug and dose or for choosing the device to be used. 


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We will administer oral hydromorphone in this study. We have selected hydromorphone because it is a prototypic, 
selective, potent, full MOR agonist that is frequently used in abuse liability studies as a surrogate for heroin, it is not 
subject to P450 metabolism, it has good oral bioavailability, there are no apparent sex effects of metabolism, it is 
used clinically for the treatment of pain, there is a wealth of literature available to which our research findings can be 
compared and interpreted, and we have several years experience administering it under double-blind, laboratory 
conditions (4, 7, 8, 128-135). The doses of hydromorphone chosen for this study are supported by a study conducted 
by Walsh et al., (2008), in which oral hydromorphone was administered to non-dependent individuals in doses up to 
25mg (136). The authors of that study had no instances of respiratory depression or reductions in Sp02 at any of the 
doses administered. That study compared the reinforcing effects of oral hydromorphone with the two prominently 
abused opioid agonists hydrocodone and oxycodone within healthy volunteers who had a history of recreational 
opioid use but were not opioid dependent. Prior to beginning the study, the researchers conducted a pilot study 
wherein 5 doses of oral hydromorphone [2.5 mg – 35mg] were administered to enable identification of several safe, 
tolerable and detectable doses for study administration. The researchers reported the 2 lowest doses [2 and 5mg] were 
inactive within a population of recreational but non-dependent individuals, and ultimately selected three mid-range 
doses [10mg, 17.5mg, 25mg] based upon evidence of safety and tolerability. 
 
We have chosen to deliver doses lower than those administered by that study so we may evaluate whether there are 
individual differences in the ability to detect the low dose of hydromorphone. Participants in our study will receive 
three active hydromorphone doses. The first dose participants will receive is the mid-level dose, which will be 
administered on study Day 2. Any participant who has a negative reaction to this dose will be discharged from the 
study. The participants will receive placebo, low, and high doses on Days 3-5 of the study; the order of doses will be 
randomized and counter-balanced. These doses were deemed safe in the same participant population in the Walsh 
study, they produced a documented detectable range of subjective effects, and they represent supratherapeutic doses 
consistent with those abused recreationally. Ultimately, we feel confident these dose values do not impose any 
unique risk above and beyond that presented by the administration of hydromorphone. 
 
Generic powdered hydromorphone will be encapsulated using size 0, opaque, hard gelatin capsules; placebo will be 
size and weight matched and will contain microcrystalline cellulose filler. A pharmacy member with no participant 
interaction will conduct the dose randomization. All medication administration will be supervised and a medical staff 
member will be available to address any adverse events or to break the medication blind. 
 
b. Justification and safety information if FDA approved drugs will be administered for non-FDA approved 
indications or if doses or routes of administration or participant populations are changed. 
 
Hydromorphone hydrochloride is a pure mu opioid agonist that can be administered in oral, rectal, intramuscular 
(IM), or intravenous (IV) formulations for the indication of acute and/or chronic pain. We have chosen to administer 
hydromorphone orally in this study to reduce the potential for side effects and adverse events associated with the 
more direct parenteral administration, and to increase the clinical relevance of the study by administering the most 
commonly-abused formulation of hydromorphone. This will also extend the time course of hydromorphone effects, 
which will help us to achieve our study aims. When administered orally, hydromorphone is rapidly absorbed through 
the gastrointestinal tract and subjected to extensive first-pass metabolism. Exposure to hydromorphone is 
proportional to the dose range, with in vivo bioavailability of an 8mg tablet being approximately 24%. Following 
oral administration, peak plasma level of hydromorphone is generally attained in 30 – 60 minutes, and approximately 
95% of hydromorphone is metabolized to hydromorphone-3-glucuronide via glucuronidation in the liver. There is no 
apparent effect of sex on the pharmacokinetics of hydromorphone. 
 
c. 
Justification and safety information if non-FDA approved drugs without an IND will be administered. 
 
N/A 
 
7. 
Study Statistics 
 
a. Primary outcome variables. The primary outcome variables are self-reported ratings of drug high and liking, 
changes in pupil diameter and blood pressure, pain threshold on 2 laboratory measures of pain, and analgesic efficacy 
in response to laboratory-induced pain. We expect that individuals with the minor allele of the A118G SNP and other 


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tagging SNPS across the OPMR1 gene will find hydromorphone more reinforcing (e.g., higher self-report ratings of 
high and drug-liking) and exhibit greater opioid-induced physiological changes (e.g., pupil diameter, blood pressure). 
Research also suggests the OPRM1 gene may also confer greater sensitivity to the negative effects of opioids, which 
may be observed as measuring greater ratings of nausea. We also hypothesize the minor allele and other tagging 
SNPs across the OPRM1 gene will produce higher pain threshold on 2 laboratory measures of pain, and lower 
analgesic efficacy in response to laboratory induced pain. 
 
b. Secondary outcome variables. Decreases in cortisol levels as a function of the degree of pleasant effects of 
hydromorphone and painful stimuli, delay-discounting curves, and the effect of sex on all outcome measures. We 
hypothesize that individuals with the minor alleles will have greater decreases in cortisol levels as a function of the 
degree of pleasant effects of hydromorphone, lower cortisol in response to painful stimuli, and steeper discounting 
curves on a delay-discounting task. Finally, although we expect that the A118G will be associated with these effects, 
we hypothesize that several of the additional OPRM1 tagging SNPs will contribute to effect magnitude. 
 
c. Statistical plan including sample size justification and interim data analysis: The aims of the proposed study will 
explore the impact of genetic variation across the OPRM1 gene on hydromorphone response. There are specific steps 
we describe below to assure that we interrogate all known functional variation across the OPRM1 gene, adequately 
cover all other variation using appropriately selected tagging SNPs, prevent spurious associations due to population 
stratification by accounting for local ancestry, and properly control the Type I error rate. 
Association Model: Our primary goal is to demonstrate the impact of SNP variation across OPRM1 on 
variability in response to hydromorphone across time and dose. Association analyses will be performed by modeling 
genotype at each SNP in a general linear model. In its simplest form this test, commonly termed the measured 
genotype analysis (137), models the influence of genotypic variation at a given locus on variation in the quantitative 
trait, essentially a one-way Analysis of Variance (ANOVA). This approach provides a distinct advantage in that it 
can easily be extended to a two-way ANOVA to model genotype effects across 3 different doses of drug. In addition, 
the flexibility of the GLM allows incorporation of ancestry covariates and environmental moderators or mediators. 
We will examine the impact of OPRM1 at each time-point in separate analyses and account for the multiple testing 
using LD-adjusted Bonferroni correction (see below). 
Power and Correction for Multiple Testing: Power (1-Type II error) and correction for multiple testing 
(control of Type I error) are important considerations in any genetic association study. Typically investigators 
attempt to control the Type I error rate of a given set of hypothesis tests by controlling the family wise error rate 
through manipulation of the alpha level of the test. This is not problematic when a handful of tests are performed at 
an alpha level (false positive level) of 5%, where the usual approach is the Bonferroni correction. We anticipate 
performing tests across multiple time-points and must adjust our target alpha level. Importantly, our 71 selected 
SNPs across the OPRM1 gene (see below) do not represent 71 independent tests due to correlation between SNPs. 
We will use an approach, termed SNPSpD (138) which uses spectral decomposition to estimate the number of 
independent tests across the region. Using available HapMap data, we estimate 44 independent tests across the 
region. We calculate power for the GLM approach modeling the effect of genotype on phenotype. If we assume a 
constant effect size difference between genotype groups (at each dose other than placebo), at an alpha level 
conservatively adjusted for 50 tests to .001, using the entire completer sample (N= 100) or the sex subsamples 
(N=50), we have >80% power for modest effect sizes of ~.45 and .67 respectively. In our calculations, effect size 
(Cohen’s d) is the mean difference between genotype groups in standard deviation units. Importantly, this effect size 
is well within the range seen by other studies examining drug response difference in OPRM1 (e.g., Ray et al., 2004: 
effect size = 1.2). 
SNP selection (for association testing and control of Local Ancestry): SNPs will be genotyped across the 
OPRM1 region to allow us to test associations across the gene and account for genetic ancestry (ethnicity). Typing all 
available SNP markers across the candidate gene set is inefficient and not necessary since many will provide 
redundant information due to linkage disequilibrium (LD). A more cost-effective strategy is to select a subset of 
representative SNPs (tagSNPs) that are in strong LD (measured through pairwise r2) with other SNPs that are 
therefore not required for genotyping in order to capture the haplotypic diversity across the gene. We followed this 
approach across OPRM1 with the Tagger algorithm at an r2 value of 0.8 and a minor allele threshold of 0.05 (139). 
We force included all predicted functional variation with allele frequency > .03 to allow for secondary hypothesis 
testing across OPRM1 functional SNPs. We used the latest Data release 21 (CEU Sample) of HapMap 
(http://www.hapmap.org) in conjunction with the NCBI build 35/hg17 of gene and EST data at UCSC Genome 
Browser (http://genome.ucsc.edu/cgi-bin/hgGateway;). Using this approach, we selected 71 SNPs across the OPRM1 
region for association testing and control of local ancestry. In our approach, we will re-estimate local ancestry for 


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each SNP association, dropping the tested SNP from ancestry estimation. Our approach to accounting for population 
stratification is detailed below. 
SNP Quality Control: Maximizing genotype accuracy is a key step in maximizing our ability to detect true 
genotype-phenotype relationships. We will perform the usual checks to ensure data precision. We will first test 
Hardy-Weinberg equilibrium (HWE) and eliminate markers that exhibit large deviations from expected genotype 
distribution. The rationale for this step is to eliminate markers that may exhibit systematic genotype error (e.g., 
excess failure of a particular allele due to allele loss). We do realize that minor deviations from HWE will be 
observed by chance when testing such a large number of markers. Thus, we will use a stringent criterion for dropping 
markers exhibiting Hardy-Weinberg disequilibrium (p < 0.001). Additionally we will eliminate markers that exhibit a 
high level (>5%) of missing data. A high level of missing data is generally interpreted as an indicator of a poor 
quality marker. We will eliminate individuals with a high level (>5%) of missing genotypes as this is likely due to 
poor DNA quality. 
Population Stratification: In the context of genetic association testing, population stratification refers to 
genetic differences between subpopulations. This is especially problematic in instances where the investigators are 
blind to the presence of stratification and/or the population substrata also differ phenotypically. In these cases, 
association analyses will be prone to generate spurious genotype-phenotype relationships. Previously, several 
methods, including genomic control (140) and STRUCTURE (141) were proposed to deal with this issue by either 
correcting the test statistic for the average level of stratification or a priori grouping of population subsets. At the 
onset of the GWAS era, the wealth of genome-wide data gave rise to additional approaches which rely on the 
correlation structure of genetic information to identify cryptic population structure. EIGENSTRAT (142) is an 
example of an approach that uses genomewide data to infer principal components of population membership. 
Recently, several investigators (143, 144) have noted that differences in global (genomewide) versus local (at a gene 
or LD block) ancestry exist, especially in admixed populations (e.g., African-American). This is particularly germane 
to our setting given: 1) the genetic ancestry of the ECA sample is a mix of European-Americans and African- 
Americans, 2) the focus on a relatively small number of genes, and 3) the lack of genome-wide SNP data. We will 
use an approach (WinPOP/LAMP; (144, 145) to estimate proportions of local ancestry at each tested gene and 
account for stratification based on those mixing proportions in subsequent GLM tests. In order to accomplish this we 
will densely tag OPRM1. 
Analysis of pain testing sessions: We hypothesize that OPRM1 SNP variants will exhibit greater pressure 
pain thresholds, greater CPM efficiency, lower hydromorphone-related analgesia, and lower cortisol stress response 
than participants with the major allele, and that results will be positively correlated with response to self-report and 
physiologically-mediated hydromorphone drug effects collected during days 3-5. Pressure pain threshold will be 
estimated by averaging the results of the 2 administrations to radiobrachialis and quadriceps muscle groups. We will 
generate a CPM index for each participant [(mean pressure pain threshold during cold pressor)/(mean pressure pain 
threshold prior to cold pressor)] x 100 (90). These values will provide a quantitative measure of percent change in 
the test stimulus (i.e., pressure point threshold). Mixed effects regression models with a random intercept will be 
used to compare dependent variables (pressure pain threshold, DNIC threshold, DNIC index) as a function of within- 
subject drug effects (placebo vs. hydromorphone), and between-subject effects of OPRM1 SNP analysis will be 
conducted as specified in Aim 1. Gender, age, and race have been associated with response to pain and the CPM test 
(146-148). Gender will be evaluated using independent subgroup analyses and age and race will be included as 
covariates. Finally, subscale scores of self-report measures of pain and coping strategies will be compared between 
the two genotype groups using independent samples t-tests, and drug identification data will be compared using a 
chi-square for each drug condition. We expect that both experimental manipulations will induce pain in the minor 
and major allele groups, and that participants with the minor allele will demonstrate lower sensitivity to pain (e.g., 
greater pressure pain magnitudes), lower NRS ratings of pain, lower cortisol response to painful stimuli, and lower 
analgesic relief from hydromorphone compared to the major allele participants. 
 
d. Early stopping rules. The safety of participants is a priority of BPRU. If a participant experiences a serious side 
effect that seems to be related to the study drug, s/he will be discontinued from the study. If clinically indicated the 
participant will be referred to the Johns Hopkins Bayview Medical Center (JHBMC) Emergency Department for 
further treatment. BPRU and the CRU have policies in place to ensure safety of all participants and staff, and some 
policies may lead to administrative discharge of a participant, and therefore, discontinuation from the study. 
Participants who do not abide by the BPRU policies and procedures, or who demonstrate behaviors abusive of staff 
or other participants may be discontinued from the study. Intercurrent illness or condition changing a participant risk 
may result in medical discharge from the study. 


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Stopping criteria for the study: In addition, an independent panel of consultants will be contracted for review 
of the risks-benefits ratio of the study. At mid-point during enrollment this panel will be provided with a report of 
adverse events and participant outcome data (subjective response to hydromorphone) by unlabeled sex groups (A vs. 
B). This information will be used to assess whether the risks reported are considered to be of unusual magnitude or 
frequency across any specific group, and to determine whether the study should be ended prematurely due to 
participant safety concerns or because a result has been unequivocally demonstrated. It is unlikely that such a small 
study would be interrupted because of a large rate of adverse events, particularly given the noninvasive 
administration method of the medication (i.e., oral) and our experience at administering this drug, however we will 
ensure that a qualified panel of reviewers makes this decision. 
 
8. 
Risks 
a. Medical risks, listing all procedures, their major and minor risks and expected frequency. 
 
Hydromorphone: Our research team has extensive experience administering hydromorphone under controlled 
laboratory conditions. Administration of any drug involves some risk because it is not always possible to predict 
individual response to drugs. The most likely risk in this study is that subjects will experience side-effects of the 
drugs that may be unpleasant. Common side effects of hydromorphone are light-headedness, dizziness, sedation, 
nausea, vomiting, sweating, flushing, dysphoria, euphoria, dry mouth, and pruritus. Less frequently observed side 
effects are weakness, headache, agitation, tremor, uncoordinated muscle movements, alterations of mood 
(nervousness, apprehension, depression, floating feelings, dreams), muscle rigidity, paresthesia, muscle tremor, 
blurred vision, nystagmus, diplopia and miosis, transient hallucinations and disorientation, visual disturbances, 
insomnia, increased intracranial pressure, flushing of the face, chills, tachycardia, bradycardia, palpitation, faintness, 
syncope, hypotension, hypertension, bronchospasm and laryngospasm, constipation, biliary tract spasm, ileus, 
anorexia, diarrhea, cramps, taste alteration, urinary retention or hesitancy, antidiuretic effects, urticaria, other skin 
rashes and diaphoresis. Side effects of hydromorphone are generally temporary, dissipate within several hours, and 
are dose-dependent. Thus, participants may only experience side-effects occasionally during the research study. 
Serious potential adverse effects of hydromorphone administration that are possible but extremely unlikely to be 
encountered in this study are respiratory depression and loss of consciousness. The most serious potential adverse 
event following hydromorphone administration is opioid agonist overdose, which is characterized by respiratory 
depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted 
pupils, and sometimes bradycardia and hypotension. In serious overdosage, particularly following intravenous 
injection, apnea, circulatory collapse, cardiac arrest and death may occur. We believe the risk of respiratory 
depression leading to overdose in this study to be low for the following reasons: we have extensive experience in the 
administration of hydromorphone, we have chosen doses that have been demonstrated directly by us in several 
previous laboratory studies (99-102) to be safe and tolerable in an identical participant population, we will exclude 
any individual who has a medical condition that may increase the risk for respiratory depression and/or other adverse 
events, all medication doses will be administered by a trained research nurse, and participants will be monitored 24- 
hours by trained staff who will have access to the opioid antagonist naloxone to reverse the opioid agonist effects. 
 
Chance That Participants May Begin Abusing Opioids Following Exposure to Study Hydromorphone: There is a 
small but potential risk that exposing non-drug abusing individuals to doses of hydromorphone designed to elicit 
reinforcing effects may precipitate subsequent drug-use behavior. Enrolling non-drug users into controlled laboratory 
studies is a conventional strategy that has been used extensively to evaluate the abuse liability potential of numerous 
drugs of abuse both within our laboratory and by other laboratories. We feel confident this strategy imposes minimal 
risk on the participants, and have provided justification for this assertion in the Protection Against Risks section. 
 
Risks Associated with Genetic Analysis: We have established several precautions to prevent breach of confidentiality 
regarding genotype status that are discussed in the Protection Against Risks section. There is a low risk for breach of 
confidentiality regarding genotype status and that a participant’s genetic information can be linked to his or her 
questionnaire assessments. 
 
Discomfort from Pain Testing: Participants will likely find the pain testing procedures uncomfortable for a brief 
period of time. This effect is expected to be transient and to produce only mild levels of discomfort. 
 
Breach of Confidentiality: Although staff members are highly trained to maintain participant confidentiality, there is 
always a risk that some of the confidential information collected could be revealed to people who are not involved in 


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the research study. This could be embarrassing to the participant if the participant preferred to keep his or her study 
participation secret, or if sensitive information became known to an individual outside the study. We have an 
extensive history of conducting research among substance abusers and have instituted several practices to prevent a 
breach from confidentiality from occurring (see below); thus, we believe this risk to be minimal. 
 
b. Steps taken to minimize the risks. 
 
Prior to study enrollment, a medical staff member carefully screens participants to exclude those with an increased 
risk of adverse events. Trained nursing staff member conducts all medication administrations, and a code to break the 
drug blinds is always available if needed. Specific protection against risks are outlined below. 
 
Protection Against Hydromorphone Risks: We also have extensive experience in the administration of 
hydromorphone and other opioid agonists in controlled laboratory settings and therefore anticipate few problems. 
Any individual who may be prone to the risks associated with hydromorphone will be excluded from participating. 
The FDA has identified the following conditions as increasing the risk for respiratory depression or other serious side 
effects following hydromorphone administration: patients with status asthmaticus; chronic obstructive pulmonary 
disease; reduced respiratory function; high blood pressure; impairment of hepatic, pulmonary or renal functions; 
myxedema or hyperthyroidism; adrenocortical insufficiency; gall bladder disease; acute alcoholism; history of 
convulsive disorders; history of head injury; currently taking sedatives, hypnotics or phenothiazines; and sulfite 
allergy. Mean exposure to hydromorphone is also increased 4-fold among patients with hepatic impairment and 3- 
fold among patients with renal impairment. Therefore, to further reduce the risk serious side effects, we will exclude 
any potential participant who exhibits one or more of these conditions. Second, although research staff and 
participants will be blinded to the exact medication provided, both groups will be informed of the potential side 
effects and risks associated with the study drug administration. Third, participants will be free to discontinue study 
participation at any time without consequence. Great care has been taken in selecting the appropriate drug doses to 
ensure hydromorphone is well-tolerated and safe for our participants. Fourth, standard concomitant medications (e.g., 
anti-nausea medications) will also be available as needed to treat any unpleasant side effects that may occur as a 
result of hydromorphone administration and participants will also be able to discontinue study participation at any 
time. Finally, the most serious risk associated with hydromorphone administration is respiratory depression. We 
believe this risk is minimal in this study for several reasons. First, we have selected a range of equipotent doses that 
we have previously demonstrated to be safe and well-tolerated in the same participant population (non opioid 
dependent individuals) (99-102) and based upon a previous study that piloted and ultimately administered identical 
doses to an identical research sample  (136). Second, we have developed several standard criteria that are followed 
by nursing staff and research personnel to monitor participants who have been provided with a study medication. All 
nursing and research staff are informed of these standards, and a list of these standards is posted in each testing room. 
The standards are as follows: If respiratory rate drops below 8 breaths/minute and is accompanied by sedation, 
participants are prompted verbally to breath. In our experience, verbal and physical stimulation is often sufficient to 
prompt breathing and restore a normal respiratory rate. If respiratory rate drops further and/or if oxygen saturation 
rates fall below 90% saturation, successive dosing is terminated. Patients are monitored carefully with a “watch and 
wait” approach; during this period they are accompanied continuously by a medical and/or nursing staff member, 
evaluated by a staff physician, and are given supplemental oxygen at 2L/min via a nasal cannula (available on site in 
the exam testing room). If clinical evaluation determines that a participant’s sedation level is increasing, the opioid 
antagonist naloxone can be promptly administered via intramuscular route to produce an immediate reversal of 
opioid effects. There have been very few incidents throughout our >15 year experience administering opioid agonists 
to human participants in controlled laboratory conditions that have necessitated actual intervention (oxygen and/or 
naloxone), however our equipment and medical/nursing staff is always prepared for this possibility. We feel these 
procedures will sufficiently protect participants from possible adverse and serious adverse events. Finally, we will 
submit an annual review of study-related adverse and serious adverse events to the Johns Hopkins IRB and an 
independent group of consultants who will serve as our data safety monitoring board for evaluation. 
 
Protection Against Chance That Participants May Begin Abusing Opioids Following Exposure to Study 
Hydromorphone: Another concern is the possibility that exposure of participants with no histories of drug abuse to 
drugs in our research setting might in some way increase the likelihood of these individuals to begin abusing illicit 
drugs when they return to the community. The Johns Hopkins IRB closely monitors this issue, and has repeatedly 
concluded that administering drugs that have reinforcing effects to individuals who do not abuse drugs is not 
associated with an increased propensity to begin abusing drugs. Administering drugs that may have reinforcing 


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effects to non-dependent users has substantial precedent in laboratory examinations of drug effects, and we have a 
rich and extensive history of utilizing this practice. Several research studies that have directly examined the 
association between study-related drug administration and subsequent drug use behavior have failed to demonstrate 
that controlled, laboratory drug exposure increases the risk for developing future dependence. For example, authors 
of a recent study that administered methamphetamine to a sample of non treatment-seeking drug abusers reported no 
difference between-group differences in drug use behaviors, assessed via the Addiction Severity Index, at a 6-month 
follow-up assessment (166). Second, a systematic follow-up study reported that alcohol-dependent volunteers 
randomly assigned to laboratory studies either involving or not involving experimental alcohol consumption have not 
differed in their follow-up outcomes (167). Third, a recent study concluded that investigational administration of 
intravenous cocaine to intravenous inexperienced cocaine users did not increase the risk of recreational intravenous 
use (168). Fourth, a study conducted by our research team administered cocaine and/or opioids to participants with 
histories of drug abuse and observed no significant changes in number of days of reported drug use, dollar amounts 
reported spent for various drug classes, or any increases in Addiction Severity Index domain scores at a one month 
follow-up (169). Finally, the College on the Problems of Drug Dependence, a prestigious international association of 
drug dependence researchers, supports the practice of enrolling non treatment-seeking individuals into drug abuse 
liability evaluation studies. Specifically, the College on Problems of Drug Dependence reported that exposure of drug 
abusers to abused drugs in a controlled research setting does not enhance the desire of an individual to use drugs, 
worsen addiction, or make addiction more difficult to treat (170). Overall, given the substantial data available in the 
literature and our own laboratory experience, we feel confident that administration of small quantities of opioids to 
individuals with recreational histories of drug abuse will not be associated with future drug use behavior. Ultimately, 
we feel the benefits of using this well-validated and heavily researched design to evaluate the association between 
OPRM1 status and abuse liability of hydromorphone outweighs the minimal potential risk that exposure to 
hydromorphone in a controlled research setting could precipitate subsequent drug use behavior. Second, the risk that 
drug administration may precipitate drug use behavior increases when the route of administration leads to a quicker 
onset of effects, as is the case with intravenous, intramuscular or intranasal administration. We have therefore chosen 
to administer hydromorphone in an oral formulation, which has the slowest onset of effects, in part to help mitigate 
this risk. Finally, both participants and research staff will be informed the study drug may consist of one or more 
numerous different drug classes (e.g., opioids, benzodiazepines, stimulants, over-the-counter medications); this is a 
widely used practice that helps reduce drug expectancy effects (97-98). This practice will also help protect against 
subsequent abuse because participants will not know exactly what compound produced the reinforcing effects they 
may have experienced. 
 
Protection Against Risks Associated with Genetic Analysis: We believe the risks associated with breach of 
confidentiality regarding genetic status to be minimal because the proposed study does not fall into any of the 
categories identified by the NIDA Genetics Workgroup as being high risk for participants involved with genetic 
studies: (1) pedigree studies that aim to discover the pattern of inheritance of a disease and to catalog the range of 
symptoms involve; (2) positional cloning studies that aim to localize and identify specific genes; (3) DNA diagnostic 
studies that aim to develop techniques for determining the presence of specific DNA mutations; and (4) gene therapy 
research that aims to develop treatments for genetic disease at the DNA level. In addition, we can identify no a priori 
defined ethical imperative that would necessitate disclosure of the genetic testing results. For instance, given the 
relatively specific eligibility criteria, it is unlikely we will be enrolling members of families. Second, there is not an 
established association between OPRM1 status and the development of any disease- including substance abuse. If 
new information becomes available that unequivocally indicates a direct link between a genetic polymorphism in the 
OPRM1 and the development of disease, we will consult with the Johns Hopkins IRB regarding any ethical 
imperative that participants be informed of their OPRM1 status. 
 
Discomfort from Pain Testing: It is likely that participants will experience some acute and transient discomfort from 
the pain testing session, however we will work to mitigate that risk as much as possible. First, participants will be 
informed of the pain testing procedure during the informed consent and will be able to make an informed decision 
regarding their study participation. Second, we chose pain tests (pressure pain and conditioned pain modulation) that 
will produce short-lived effects, and are unlikely to produce any residual pain. Third, we will stop pain 
administration as soon as participants report the first incidence of “pain” (operationalized as 50% on a scale of 0% 
(no pain) to 100% (extreme pain)). Time to first pain will serve as our dependent variable in the analyses. Fourth, we 
will enforce an upper limit on both pain measures to prevent any tissue damage from occurring (e.g., hand cannot be 
in cold pressor task for >150 seconds). Fifth, participants will be informed that they can revoke their consent to 
participate in the pain testing at any time without penalty. Finally, the participants will be monitored 24 hours by 


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study staff and will have access to medical care and concomitant medications to treat residual pain if necessary. We 
will also document and submit to our DSMB all adverse events reported from the pain testing session and will follow 
any recommendations they may have regarding the cessation of pain testing. 
 
Protection Against Risks Associated with Confidentiality: To protect confidentiality, all research participants will be 
assigned unique participant identification codes that will be used on all study–related forms and online websites. 
Documents that include the participants’ full names (e.g., signed informed consent forms) will be stored in an 
independent binder, consistent with FDA Good Clinical Practice Guidelines, and will be kept in a locked room. 
Confidential information will never be shared with anyone outside of the research program without the explicit 
written permission of the research participant. Only selected designated staff members will be approved to share 
confidential information after explicit written permission is obtained from the participant and the participant will be 
able to revoke written permission at any time. In accordance with IRB requirements, all research staff will be 
formally trained in these procedures. No identifying participant information will be used in written reports, 
manuscripts and/or conference presentations. 
 
c. Plan for reporting unanticipated problems or study deviations.: 
All adverse events will be reported to the IRB and other relevant agencies (e.g., FDA, NIDA) as required and as 
described in the DSMP. The Principal Investigator and Co-investigators are responsible for reporting such events. 
 
d. Legal risks such as the risks that would be associated with breach of confidentiality.: 
Although there is always a small risk that confidentiality will be breached, we believe this risk to be very minimal 
with the current study. 
e. Financial risks to the participants. None. 
 
9. 
Benefits 
Description of the probable benefits for the participant and for society: The long-term goal of this research is 
to investigate individual differences in response to opioids, and identify genetic differences that contribute to 
variations in the susceptibility of opioid dependence. The objective of this application is to determine whether the 
OPRM1 gene predict one of several opioid-mediated effects using a rigorous, controlled laboratory study among 
healthy individuals with no history of drug dependence and whether this effect differs as a function of gender. This 
study will constitute the most controlled, rigorous, comprehensive examination of the OPRM1 gene association with 
opioid-mediated effects to date. We expect that genotype will be associated with several opioid-mediated effects. 
These results are expected to have a positive impact by advancing our understanding of the association between the 
OPRM1 gene and opioid-mediated effects, including susceptibility for opioid dependence. These data will provide 
positive contributions to the field of pharmacogenomic medication prescribing, the development of opioid 
dependence prevention strategies and interventions to treat comorbid pain and opioid dependence, and will have 
implications for other MOR-mediated effects, including alcohol dependence. 
 
 
10. 
Payment and Remuneration 
a. 
Detail compensation for participants including possible total compensation, proposed bonus, and any 
proposed reductions or penalties for not completing the protocol. 
 
Participants will be paid $30 for completing the 
Screening visit. Enrolled participants will earn $50 for 
each session day and will incur a completion bonus that 
will escalate in value with each subsequent session. 
Bonuses will be earned for completion of the study only 
and any participant who ends the study prematurely will 
receive their session payments but will forfeit the 
completion bonus. Participants can earn up to $750 in payments and bonuses for study participation. 
 
11. 
Costs 
a. 
Detail costs of study procedure(s) or drug (s) or substance(s) to participants and identify who will 
pay for them. 
Study Day 
Session Payment 
Completion Bonus 
Admission 
$50.00 
$50.00 
Day 2 
$50.00 
$75.00 
Day 3 
$50.00 
$100.00 
Day 4 
$50.00 
$125.00 
Day 5 
$50.00 
$150.00 
Total: 
$250.00 
$500.00 
$750.00 


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All study procedures and study drug will be supported by a grant from the National Institute on Drug Abuse and will 
be provided to participants free of charge. 


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82. Finan PH, Zautra AJ, Davis MC, Lemery-Chalfant K, Covault J, Tennen H. Genetic influences on the dynamics 
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86. Fukuda K, Hayashida M, Ide S, Saita N, Kokita Y, Kasai S, Nishizawa D, Ogai Y, Hasegawa J, Nagashima M, 
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88. Campa D, Gioia A, Tomei A, Poli P, Barale R. Association of ABCB1/MDR1 and OPRM1 gene polymorphisms 
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89. Hayashida M, Nagashima M, Satoh Y, Katoh R, Tagami M, Ide S, Kasai S, Nishizawa D, Ogai Y, Hasegawa J, 
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ICF_001.pdf: 
Date: October 29, 2019 
Principal Investigator: Kelly Dunn, Ph.D. 
Application No.: IRB00047423 
Approved October 29, 2019 
Page 1 of 11 
Combined Informed Consent/Authorization June 2015 Version 15 
 
 
 
 
 
 
NCT: 02360371 
 
Title: A118G SNP and OPRM1 Gene Opioid-mediated Effects in 
Humans 
 
PI: Kelly Dunn, Ph.D., MBA 
 
Document Date: October 29, 2019 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Date: October 29, 2019 
Principal Investigator: Kelly Dunn, Ph.D. 
Application No.: IRB00047423 
Approved October 29, 2019 
Page 2 of 11 
Combined Informed Consent/Authorization June 2015 Version 15 
 
 
 
 
RESEARCH PARTICIPANT INFORMED CONSENT AND PRIVACY 
AUTHORIZATION FORM 
 
Protocol Title: 
Individual Differences in Drug Response 
Application No.: 
IRB00047423 
Sponsor: 
National Institute on Drug Abuse 
 
Principal Investigator: Kelly Dunn, Ph.D. 
5510 Nathan Shock Drive 
Baltimore MD 21224 
Phone: 410-550-2254; Fax: 410-550-0030 
 
1. 
What you should know about this study: 
• You are being asked to join a research study. This consent form explains the research study and your 
part in it. Please read it carefully and take as much time as you need. Ask your study doctor or the 
study team to explain any words or information that you do not understand. 
• You are a volunteer. If you join the study, you can change your mind later. There will be no penalty 
or loss of benefits if you decide to quit the study. 
• During the study, we will tell you if we learn any new information that might affect whether you 
wish to continue to participate. 
• If we think your participation in this study may affect your clinical care, information about your 
study participation will be included in your medical record, which is used throughout Johns Hopkins. 
Doctors outside of Johns Hopkins may not have access to this information. You can ask the research 
team to send this information to any of your doctors. 
• When Johns Hopkins is used in this consent form, it includes The Johns Hopkins University, The 
Johns Hopkins Hospital, Johns Hopkins Bayview Medical Center, Howard County General Hospital, 
Johns Hopkins Community Physicians, Suburban Hospital, Sibley Memorial Hospital and All 
Children’s Hospital. 
• Biospecimens will be collected in this study. Biospecimens may include any of the following: 
blood, tissue, saliva, urine, bone marrow, cells, etc. Most biospecimens contain DNA, which is the 
genetic code for each person. 
• A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by 
U.S. Law. This Web site will not include information that can identify you. At most, the Web site 
will include a summary of the results. You can search this Web site at any time. 
• If you would like to review the information for this study, or a summary of the results, ask the study 
team doctor for the ClinicalTrials.gov study registration number. 
If you are using Epic for this study, fax a copy 
of the signed consent form to 410-367-7382. 
Patient I.D. Plate 


Date: October 29, 2019 
Principal Investigator: Kelly Dunn, Ph.D. 
Application No.: IRB00047423 
Approved October 29, 2019 
Page 3 of 11 
Combined Informed Consent/Authorization June 2015 Version 15 
 
 
• During this study, you will not have access to certain medical information and test results collected 
for study purposes. If an emergency occurs while you are in the study, medical information needed 
for your treatment can be made available to your study physician and other physicians who treat you. 
When the study is completed, all the information in your medical record will be available to you. 
 
2. 
Why is this research being done? 
This research is being done to learn more about how people respond to different types of drugs, 
including how they feel in response to the drugs, as well as how their body may respond to the drugs. 
 
We know that not all medicines work for all people, and not all people experience the same good or bad 
effects. Scientists now know that certain genes (the material in the cells that is inherited and is made of 
DNA) may in part be responsible for how drugs are handled by the body, as well as for the drugs’ 
effects, good and bad. This research will help us understand how and why medicine may or may not 
work for specific people. We hope this research will help improve doctors’ ability to prescribe the right 
drug to patients. 
 
People who are healthy may join this study. 
 
How many people will be in this study?: 
Our goal is to enroll and complete 100 people in this study. 
 
3. 
What will happen if you join this study? 
If you agree to be in this study, we will ask you to do the following things: 
 
Screening Visit: 
You will be completing the Screening visit today. The goal of this visit will be to determine whether 
you’re eligible for the study. During the visit, we will ask you a series of questions and will collect a 
blood sample (no more than 2 tablespoons) and urine sample from you to ensure it is safe for you to be 
enrolled into the study. As mentioned during the phone interview, you will also meet with a medical 
staff member to complete a brief history and physical either during this Screening visit or during Study 
Day 1. 
 
Once you complete the Screening visit, we will notify you whether you are eligible to join the study. 
Women will also be asked to keep a log of their menstrual cycle, which will help determine the day on 
which they will be admitted into the study. 
 
Study Visits: 
Next, we will schedule a time for you to be admitted to a clinical research unit, where you will stay for a 
total of 5 days. While you are on the unit, you will be provided scrubs to wear and (if you are a smoker) 
will be able to smoke cigarettes. You will be admitted to the unit on Study Day 1 and will have that day 
to adjust to being on the unit. We will also introduce you to the tasks and questionnaires that we will ask 
you to complete during the rest of the study days so that you will feel completely comfortable with 
everything before any study-related activities begin. 
 
Request to collect and store biospecimens for future research 
As part of this study, we will collect a blood sample that will be analyzed for different genetic 
information. You will not be informed of the results of these tests because, as of now, there are no 
known links to the genes being tested and any clinical conditions. 


Date: October 29, 2019 
Principal Investigator: Kelly Dunn, Ph.D. 
Application No.: IRB00047423 
Approved October 29, 2019 
Page 4 of 11 
Combined Informed Consent/Authorization June 2015 Version 15 
 
 
The Genetic Information Nondiscrimination Act (GINA) may help protect you from health insurance or 
employment discrimination based on genetic information. 
 
The law provides that health insurance companies and group health plans 
• may not ask for genetic information from this research and 
• may not use genetic information when making decision about eligibility or premiums 
 
The law will not stop health insurance companies from using genetic information to decide whether to 
pay claims. The law does not apply to other types of insurance (such as: life, disability or long-term 
care). 
 
As part of this research study, we would like to ask you to let us collect an additional sample (no more 
than 2 tablespoons) and let us store your biospecimens and health information for future research. This 
research could include other diseases and involve research tools such as gene sequencing or the creation 
of cell lines. 
 
• Gene sequencing of your DNA provides researchers with the code to your genetic material. 
 
• Cell lines are living tissue samples that can be grown in a laboratory. A cell line can provide 
an unlimited supply of cells in the future without requiring more samples from you. Each 
cell contains your complete DNA. 
 
The study doctor can provide you with additional information if you have questions. Also, further 
information about our use of your biospecimens can be found in this consent document under the 
heading What happens to Data and Biospecimens that are collected in the study?. 
 
Will you allow us to store the biospecimens we collect for this study for use in future research? 
 
YES    
 
NO     
 
Signature of Participant 
Signature of Participant 
 
 
Study Days 2-5: 
At the beginning of each session during Study Days 2-5, you will be given a pill that may contain a 
prescription stimulant, a benzodiazepine (e.g., anti-anxiety medication), an opioid (e.g., a pain 
medication), an over-the-counter medication, or a placebo (contains no medication, like a sugar pill). 
Neither you nor the staff member administering the pill will know what the pill contains. After you take 
the pill, you will be asked to complete several questions about how the pill makes you feel, and you will 
complete these questionnaires several times up to 6 hours after you take the pill. We will also collect a 
saliva sample from you at multiple points during the day that will be tested for levels of stress hormones, 
and will ask you to complete computerized tasks. In addition, you will be asked to complete a pain 
testing session. For this session you will be asked to place your arm and/or hand into cold water. This 
may be mildly painful, however you will be able to remove your arm/hand whenever you want. A staff 
member will also place a small device on some of your muscles, this device will make you feel some 
pressure on those muscles. This procedure may also be mildly painful, and you will be able to end the 
procedure whenever you wish. Finally, we will tap your hand with some pencil-like objects. This may 
be mildly painful, but again you will be able to stop the task whenever you want. Finally, at some point 
during your study participation we will collect a blood sample (no more than 1 tablespoon) that will be 
used to analyze your metabolic status. 


Date: October 29, 2019 
Principal Investigator: Kelly Dunn, Ph.D. 
Application No.: IRB00047423 
Approved October 29, 2019 
Page 5 of 11 
Combined Informed Consent/Authorization June 2015 Version 15 
 
 
You will be discharged at the end of Day 5 after you complete the sessions for that day and are able to 
pass a sobriety test that indicates you are not under the influence of any drugs. If you are unable to 
complete the sobriety test, you will remain in the unit until you can pass the test, or until the following 
day if necessary. 
 
How long will you be in the study? 
You will be in this study for 5 days. 
 
Request to re-contact you for future research 
We would also like to store the information that you provide to us so that we may re-contact you in the 
future to ask if you’d like to learn about additional research opportunities. This does not mean you 
would have to participate in any additional research, that is a separate decision that you would make at 
another time. Rather, it will give us permission to contact you about research for which we believe you 
may be interested and/or eligible, based on the responses that you provide to us during this study. You 
are free to chose whether we can contact you or not, and your choice will not impact your ability to be 
enrolled into this study. 
 
Would you like us to contact you in the future regarding new research opportunities? 
 
YES    
 
NO     
 
Signature of Participant 
Signature of Participant 
 
4. 
What are the risks or discomforts of the study? 
 
Study Drug: 
The largest risk of this study is associated with the medication(s) you will receive. Side effects of the 
medication(s) you will be receiving are expected to be mild and short-lived. You will be screened before 
enrolling in the study to ensure you are at a low risk of experiencing any study drug-related side effects. 
Below we list the side effects that you may experience from the study medication and the percent of 
people who experience these side effects from any formulation of the medication. The severity of the 
symptoms increases as you move down the list: 
 
• Dermatologic: Flushing (2% of people), Pruritus (“itchy skin”, 1-8%) 
• Gastrointestinal: Constipation (7-31%), Nausea (9-28%), Vomiting (6-14%) 
• Cardiovascular: Hypotension (“low blood pressure”, less than 2%), Syncope (“fainting”, less than 
2%) 
• Neurologic: Asthenia (“weakness”, 1-11%), Dizziness (1-11%), Headache (1-12%), Somnolence 
(“sleepiness”, less than 2%), Coma (less than 2%), Myoclonus (“jerking of muscles”, less than 2%), 
Raised intracranial pressure (less than 2%) 
• Psychiatric: Suicidal thoughts (less than 2%) 
• Respiratory: Apnea (“brief stop in breathing”, less than 1%), Respiratory Arrest or Depression 
(“stopping breathing”, less than 2%) 
• Other: Drug dependence/Addiction (less than 1%), Drug Withdrawal (less than 1%) 
 
It is important for you to know that, in extreme cases, these medications may cause respiratory 
depression or arrest, severe allergic reaction, or even death. You will undergo extensive medical testing 
during the Screening visit to identify whether you have any of the risk factors that would increase the 
likelihood that you would have an extreme reaction to the study medication and will not be enrolled into 
the study if we have any reason to believe that the study medication would put you at undue risk. 


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Pain Testing: 
You will likely experience some discomfort from the pain testing procedures that are conducted during 
the study. The pain is expected to be mild and short-lived, and you will be able to end your participation 
in the pain sessions at any time. 
 
Genetic Testing: 
We will collect a blood sample that will be tested for your genetic background. Despite the GINA 
protections and the best efforts of the research team, there may still be a risk if information about you 
were to become known to people outside of this study. 
 
Genetic information is unique to you, even without your name or other identifiers. For this reason, 
genetic information like DNA may be used to identify you and possibly your family members. We have 
procedures (such as, labeling your biospecimens with a password protected code known only to select 
research staff) to prevent people working with your DNA from discovering if it belongs to you. 
However, there is the risk this can happen as new ways of tracing genetic information are being 
developed that may make re-identification of genetic information possible. 
 
Blood Draw: 
We will use a needle to draw blood from you. Taking blood may cause discomfort, bleeding, or bruising 
where the needle enters the body. In rare cases, it may result in fainting. There is a small risk of 
infection. 
 
Study Questionnaires: 
You may get tired or bored when we are asking you questions or you are completing questionnaires. 
You do not have to answer any question you do not want to answer. 
 
There may be additional side effects and discomforts that are not yet known. 
 
5. 
Are there risks related to pregnancy? 
This research may hurt an embryo or fetus in ways we do not currently know. To protect against this 
risk, we will test all women for pregnancy before joining the study and will ask women to keep a log of 
their menstrual cycle before they are admitted into the study. 
 
6. 
Are there benefits to being in the study? 
There is no direct benefit to you from being in this study. However, your participation in this study will 
help us to learn more about how individual people respond to different types of medications. This will 
help improve our ability to select appropriate medications for persons, to prevent us from needing to try 
several medications before finding one that works well. 
 
If you take part in this study, you may help others in the future. 
 
7. 
What are your options if you do not want to be in the study? 
You do not have to join this study. If you do not join, your care at Johns Hopkins will not be affected. 
 
8. 
Will it cost you anything to be in this study? 
No. 


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9. 
Will you be paid if you join this study? 
You will be compensated for your time in the study. You will be paid $30 for completing this Screening 
visit. You will also earn $50 for each session day, and will earn a bonus payment for each day you 
remain in the study. The bonus will be paid only to those individuals who remain in the study for the 
entire 5 days. Table 1 shows you the payment schedule for the study, you can earn up to $750 in study 
payments for Days 1-5. 
 
Study Day 
Session Payment 
Completion Bonus 
Admission 
$50.00 
$50.00 
Day 2 
$50.00 
$75.00 
Day 3 
$50.00 
$100.00 
Day 4 
$50.00 
$125.00 
Day 5 
$50.00 
$150.00 
Total: 
$250.00 
$500.00 
$750.00 
You may be required to provide your social security number to be paid for taking part in this study. 
Federal tax law requires that you report your research payments when you file your taxes. If your total 
payments from Johns Hopkins exceed $600 per year, Johns Hopkins will report these payments to the 
Internal Revenue Service and you will receive a 1099-MISC form from us. 
 
10. 
Can you leave the study early? 
• You can agree to be in the study now and change your mind later. 
• If you wish to stop, please tell us right away. 
• Leaving this study early will not stop you from getting regular medical care. 
• If you decide to leave early, we will ask you to complete a sobriety test to ensure you are not under 
the effects of any drugs; if you fail this test we may ask you to stay until you complete the test 
safely. 
 
If you leave the study early, Johns Hopkins may use or give out your health information that it has 
already collected if the information is needed for this study or any follow-up activities. 
 
11. 
Why might we take you out of the study early? 
You may be taken out of the study if: 
• Staying in the study would be harmful. 
• You need treatment not allowed in the study. 
• You fail to follow instructions. 
• You become pregnant. 
• The study is cancelled. 
• There may be other reasons to take you out of the study that we do not know at this time. 
 
If you are taken out of the study early, Johns Hopkins may use or give out your health information that it 
has already collected if the information is needed for this study or any follow-up activities. 
 
12. 
How will your privacy be protected? 
We have rules to protect information about you. Federal and state laws and the federal medical Privacy 
Rule also protect your privacy. By signing this form you provide your permission, called your 
“authorization,” for the use and disclosure of information protected by the Privacy Rule. 


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The research team working on the study will collect information about you. This includes things learned 
from the procedures described in this consent form. They may also collect other information including 
your name, address, date of birth, and information from your medical records (which may include 
information about HIV, drug, alcohol or STD treatment, genetic test results, or mental health treatment). 
 
The research team will know your identity and that you are in the research study. Other people at Johns 
Hopkins, particularly your doctors, may also see or give out your information. We make this information 
available to your doctors for your safety. 
 
People outside of Johns Hopkins may need to see or receive your information for this study. Examples 
include government agencies (such as the Food and Drug Administration), safety monitors, other sites in 
the study and companies that sponsor the study. If you are in a cancer study that receives federal 
funding, the National Cancer Institute (NCI) now requires that we report identifiable information (such 
as, zip code) about your participation. You may contact the NCI if you have questions about how this 
information is used. 
 
We cannot do this study without your authorization to use and give out your information. You do not 
have to give us this authorization. If you do not, then you may not join this study. 
 
We will use and disclose your information only as described in this form and in our Notice of Privacy 
Practices; however, people outside Johns Hopkins who receive your information may not be covered by 
this promise or by the federal Privacy Rule. We try to make sure that everyone who needs to see your 
information keeps it confidential – but we cannot guarantee that your information will not be re- 
disclosed. 
 
The use and disclosure of your information has no time limit. You may revoke (cancel) your permission 
to use and disclose your information at any time by notifying the Principal Investigator of this study by 
phone or in writing. If you contact the Principal Investigator by phone, you must follow-up with a 
written request that includes the study number and your contact information. The Principal 
Investigator’s name, address, phone and fax information are on page one of this consent form. 
 
If you do cancel your authorization to use and disclose your information, your part in this study will end 
and no further information about you will be collected. Your revocation (cancellation) would not affect 
information already collected in the study, or information we disclosed before you wrote to the Principal 
Investigator to cancel your authorization. 
 
13. 
What if there is a Certificate of Confidentiality for this study? 
The National Institutes of Health has given us a Certificate of Confidentiality for this study. This 
Certificate provides some additional protection for research information that identifies you. The 
Certificate allows us, in some circumstances, to refuse to give out information that could identify you as 
a research subject without your consent, when such information is sought in a federal, state, or local 
court or public agency action. Still, we may disclose identifying information about you if, for example, 
you need medical help. 
 
We may also disclose identifiable information about you as described in Section 12 of this form or in 
other cases. For example, the government may see your information if it audits us, and the research team 
will voluntarily comply with reporting requirements to the appropriate local or state authorities: 
 
• if they suspect abuse, neglect or abandonment of a child or vulnerable or dependent adult; 
• if certain diseases are present; and 


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• if the team learns that you plan to harm someone. In this case, the team also may warn the person 
who is at risk. 
 
Even with this Certificate in place, you and your family members must continue to protect your own 
privacy. If you voluntarily give your written consent for an insurer, employer, or lawyer to receive 
information about your participation in the research, then we may not use the Certificate to withhold this 
information. 
 
This Certificate does not mean the government approves or disapproves of this research project. 
 
14. 
What treatment costs will be paid if you are injured in this study? 
Johns Hopkins and the federal government do not have programs to pay you if you are hurt or have 
other bad results from being in the study. However, medical care at Johns Hopkins is open to you as it 
is to all sick or injured people. 
 
• If you have health insurance: The costs for any treatment or hospital care you receive as the result of 
a study-related injury will be billed to your health insurer. Any costs that are not paid for by your 
health insurer will be billed to you. 
 
• If you do not have health insurance: You will be billed for the costs of any treatment or hospital care 
you receive as the result of a study-related injury. 
 
By signing this form you will not give up any rights you have to seek compensation for injury. 
 
15. 
What other things should you know about this research study? 
 
a. What is the Institutional Review Board (IRB) and how does it protect you? 
The Johns Hopkins Medicine IRB is made up of: 
• Doctors 
• Nurses 
• Ethicists 
• Non-scientists 
• and people from the local community. 
 
The IRB reviews human research studies. It protects the rights and welfare of the people taking part 
in those studies. You may contact the IRB if you have questions about your rights as a participant or 
if you think you have not been treated fairly.  The IRB office number is 410-955-3008. You may 
also call this number for other questions, concerns or complaints about the research. 
 
When the Johns Hopkins School of Medicine Institutional Review Board (IRB) reviews a study at 
another site, that site (institution) is solely responsible for the safe conduct of the study and for 
following the protocol approved by the Johns Hopkins IRB. 
 
b. What do you do if you have questions about the study? 
Call the principal investigator, Dr. Kelly Dunn at 410-550-2254. If you wish, you may contact the 
principal investigator by letter or by fax. The address and fax number are on page one of this 
consent form. If you cannot reach the principal investigator or wish to talk to someone else, call the 
IRB office at 410-955-3008. 


Date: October 29, 2019 
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c. What should you do if you are injured or ill as a result of being in this study? 
If you think you are injured or ill because of this study, call Dr. Eric Strain, M.D. or Dr. Denis 
Antoine, M.D. at 410-550-0052 during regular office hours. 
 
d. What happens to Data and Biospecimens that are collected in the study? 
Johns Hopkins and our research partners work to understand and cure diseases. The biospecimens 
and/or data you provide are important to this effort. 
 
If you join this study, you should understand that you will not own your biospecimens or data, and 
should researchers use them to create a new product or idea, you will not benefit financially. 
 
With appropriate protections for privacy, Johns Hopkins may share your biospecimens and 
information with our research sponsors and partners. 


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16. 
What does your signature on this consent form mean? 
Your signature on this form means that: You understand the information given to you in this form; you accept the 
provisions in the form and you agree to join the study. You will not give up any legal rights by signing this 
consent form. 
 
 
WE WILL GIVE YOU A COPY OF THIS SIGNED AND DATED CONSENT FORM 
 
 
 
 
Signature of Participant 
(Print Name) 
Date/Time 
 
 
 
Signature of Person Obtaining Consent 
(Print Name) 
Date/Time 
 
 
 
 
 
NOTE: A COPY OF THE SIGNED, DATED CONSENT FORM MUST BE KEPT BY THE PRINCIPAL INVESTIGATOR; A COPY MUST BE GIVEN 
TO THE PARTICIPANT; IF YOU ARE USING EPIC FOR THIS STUDY A COPY MUST BE FAXED TO 410-367-7382; IF YOU ARE NOT USING EPIC 
A COPY MUST BE PLACED IN THE PARTICIPANT’S MEDICAL RECORD (UNLESS NO MEDICAL RECORD EXISTS OR WILL BE CREATED). 
 
ONLY CONSENT FORMS THAT INCLUDE THE JOHNS HOPKINS MEDICINE LOGO CAN BE USED TO OBTAIN THE CONSENT OF RESEARCH 
PARTICIPANTS. 


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DOCUMENTATION OF PHYSICIAN/MID-LEVEL PROVIDER CONSENT 
 
 
My signature below indicates that I have discussed the risks, benefits, and alternatives, answered any 
questions, and believe the participant is able to make an informed choice to join the study. 
 
 
 
 
Signature of Physician/Mid-Level Provider 
(Print Name) 
Date/Time 
 
 
 
 
Signature of Participant 
(Print Name) 
Date/Time 
 
 
 
 
 
NOTE: A COPY OF THE SIGNED, DATED CONSENT FORM MUST BE KEPT BY THE PRINCIPAL INVESTIGATOR; A COPY MUST BE GIVEN 
TO THE PARTICIPANT; IF YOU ARE USING EPIC FOR THIS STUDY A COPY MUST BE FAXED TO 410-367-7382; IF YOU ARE NOT USING EPIC 
A COPY MUST BE PLACED IN THE PARTICIPANT’S MEDICAL RECORD (UNLESS NO MEDICAL RECORD EXISTS OR WILL BE CREATED). 
 
 
ONLY CONSENT FORMS THAT INCLUDE THE JOHNS HOPKINS MEDICINE LOGO CAN BE USED TO OBTAIN THE CONSENT OF RESEARCH 
PARTICIPANTS.