Conditions: Pain Cannabis Opioid Use
Keywords: Clinical Trial Analgesia Phase II Abuse potential
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 31
Healthy volunteers: yes

Brief summary:
This is a single-group, within-subject, double-blind, double-dummy, placebo and active-controlled study evaluated whether the FDA-approved cannabinoid cannabidiol (CBD; Epidiolex) would enhance analgesia, subjective reports, and cognitive performance when compared to the FDA-approved opioid hydromorphone (Dilaudid). This is study 2 is a series of studies.

Detailed description:
This was a human laboratory systematic examination of whether adding the FDA-approved cannabinoid cannabidiol (CBD; Epidiolex; oral) to the FDA-approved opioid hydromorphone (Dilaudid; oral) would change the experience of hydromorphone as rated by laboratory measures of pain, subjective reports of drug effects, and cognitive performance. Subjects are healthy individuals with no history of drug use disorder. Study subjects and staff were completed blinded to the study drugs and the class of drugs under investigation and were informed that subjects may receive opioids, stimulants, cannabinoids, benzodiazepines, over the counter medications, and/or placebo. All participants completed all sessions. Sessions lasted up to 8-hours and were conducted at least 7 days apart on an outpatient basis. Primary outcomes were collected from participants prior to dosing and at several hour periods post-dosing.

Arms:
arm 1: Within-subject double-blind, double-dummy administration of placebo + placebo. Order of dose randomized session days 2-5. arm 2: Within-subject double-blind, double-dummy administration of hydromorphone (oral) 4mg + placebo. Always administered during session 1. arm 3: Within-subject double-blind, double-dummy administration of hydromorphone (oral) 4mg + cannabidiol (oral) 50mg. Order of dose randomized session days 2-5. arm 4: Within-subject double-blind, double-dummy administration of hydromorphone (oral) 4mg + cannabidiol (oral) 100mg. Order of dose randomized session days 2-5. arm 5: Within-subject double-blind, double-dummy administration of hydromorphone (oral) 4mg + cannabidiol (oral) 200mg. Order of dose randomized session days 2-5.

Interventions: intervention 1: Within-subject test of blinded study medications
Intervention descriptions: intervention 1: Within-subject double-blind, double-dummy, study design wherein all participants received all doses in 8-hour outpatient sessions. Primary outcomes assessed during 8-hour outpatient sessions and included laboratory pain testing, subjective reports of drug effects, and cognitive performance, evaluated as a function of study medication condition.

Protocol document:
Prot_SAP_000.pdf: 
Evaluating Cannabidiol (CBD) to Enhance the Analgesic
Effect of Hydromorphone in Humans
NCT: 04036968
Protocol Date: October 18, 2021
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Date: October 18, 2021
Principal Investigator: Kelly Dunn, Ph.D.
Application Number: IRB00214289
JHM IRB - eForm A – Protocol
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a section is not applicable, leave heading in and insert N/A.
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When submitting JHM IRB eForm A (new or revised), enter the date submitted to the field at the top
of JHM IRB eForm A.
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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.
This study will systematically evaluate whether cannabinoids can enhance the analgesic efficacy of opioids, which
will advance the use of cannabinoids for the treatment of acute and/or chronic pain. Chronic pain affects over 100
million Americans. Opioids are unanimously recognized as the most effective drugs for the relief of pain and
suffering, but the US is now suffering from an epidemic of abuse, addiction and accidental deaths resulting from the
increased sale and use of opioids. There is legitimate value in identifying adjuncts that might reduce reliance on
opioids while maintaining adequate pain relief. Preclinical studies report that co-administering cannabinoids with
opioid agonists significantly and reliably reduce the amount of opioids required for analgesiabut this hypothesis has
not been rigorously evaluated in humans. This proposal will evaluate the effect of cannabidiol (CBD; Epidiolex) on
opioid-induced analgesia. The study will aim to complete 40 healthy adults (20 men/women) through a within-
subject, dose-response evaluation of cannabinoids on the analgesic effect of hydromorphone (Dilaudid). Subjects will
complete 5 experimental sessions that will occur at least once weekly and will enable subjects to admit themselves
into a clinical research unit the night before the session to complete the study session as needed. Subjects will receive
a dose of hydromorphone (4mg, oral) and a double-blind oral dose of study drug or placebo the morning of each
experimental session, and will undergo quantitative sensory testing (QST; a comprehensive pain testing battery),
provide self-report ratings of drug effects, and complete a neurocognitive battery. QST testing will comprehensively
and systematically measure pain sensitivity, and provide information on the full range of analgesic effects possible
across a wide variety of pain measures, including threshold responses (thermal, pressure), temporal summation, cold
pressor, conditioned pain modulation, and capsaicin sensitization. Primary outcomes will be magnitude and duration
of pain as a function of study drug dose. Additional primary aims include proxy measures of abuse liability and
neurocognitive performance. All measures will be assessed as a function of sex, due to substantial evidence that
men/women differ with regard to pain perception, endogenous cannabinoid receptor density, and opioid response.
We hypothesize that cannabinoids will shift the analgesic curve of hydromorphone and enhance analgesia effects.
Results from this study will help advance the acceptance of cannabinoids from use with only treatment-refractory
pain conditions to widespread societal use for clinical pain.
2.
Objectives (include all primary and secondary objectives)
1. Primary Aim 1: Evaluate the magnitude and duration of combined cannabidiol and hydromorphone
to reduce pain sensitivity in a validated model of pain. We hypothesize that the addition of a cannabidiol
to hydromorphone will result in a dose-dependent increase in the magnitude and duration of analgesia in
patients undergoing a validated laboratory model of pain.
2. Primary Aim 2: Evaluate the subjective responses to combinations of cannabidiol and hydromorphone
to determine the subjective, euphoric effects of the combination products. We hypothesize that
cannabidiol will not increase the subjective ratings of positive drug effects or other proxy measures of abuse
liability, relative to hydromorphone alone.
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3. Primary Aim 3: Evaluate the degree to which combining cannabidiol with hydromorphone impacts
neurocognitive performance. We hypothesize that cannabidiol may reduce neurocognitive performance at
high doses, relative to hydromorphone alone, though the degree to which this may occur is unknown. This
aim is critical for the advancement of potential opioid/cannabinoid combination products.
4. Secondary Aim 1: Evaluate whether there are sex differences on study outcomes. We hypothesize that
cannabidiol enhancement of hydromorphone-analgesia will be greater among female vs. male subjects.
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).
This study will systematically evaluate whether cannabinoids can enhance the analgesic efficacy of opioids, which
will advance the use of cannabinoids for the treatment of acute and/or chronic pain.
Scope of the problem: Chronic pain affects over 100 million Americans - more than diabetes, heart disease,
and cancer combined1. It exacts substantial suffering, physical disability, and is incredibly costly. Persistent pain
profoundly impairs quality of life2;3 and increases risk for medical4 and psychiatric morbidity5. Medical providers
have an obligation to treat their patient’s pain and opioids are unanimously recognized as the most effective drugs for
the relief of pain and suffering6. Opioids are the 3rd most widely prescribed category of medication in the US,
however with increases in availability we have seen substantial increases in corresponding problems, most notably
opioid-related overdose deaths. Accidental poisonings are now the leading cause of accidental death in adults aged
25-647, and 72% of overdose deaths involve opioid analgesics,8 a higher prevalence than deaths from heroin and
cocaine combined9-11. Improper use of prescription painkillers results in an estimated $72.5 billion annually in direct
health care costs,12 which does not include societal costs like social services, law enforcement, and lost productivity.
The phenomena associated with high dosing, abuse, and addiction continues to challenge the clinical community and
poses an important question to the scientific community – is there a method to enhance opioid prescribing
requirements while maintaining adequate pain relief?
Potential to combine cannabinoids with opioids for pain relief: Population based studies in fibromyalgia,
arthritis, muscular sclerosis and spinal cord injury have all described cannabis use for pain relief 13. Currently, 12-15%
of the population uses medicinal cannabis and the most commonly cited reason is for chronic pain14. A systematic
review reported that >80% of trials demonstrated a significant analgesic effect of cannabinoid relative to placebo15 and
the endocannabinoid system (ECS) offers a strong mechanistic rationale for the pain reducing actions of
cannabinoids16. Further, there is now substantial preclinical evidence in rodents119-122 (Cichewicz, Martin, Smith, &
Welch, 1999; Finn et al., 2004; Smith, Cichewicz, Martin, & Welch, 1998; Welch & Stevens, 1992; Williams et al., 2006) and
primates123-125 that cannabinoids and opioids, when administered together, are extremely effective in reducing pain,
with up to a 20-fold increase in efficacy, suggesting that these two medications may have a synergistic effect on pain.
The CB1 receptor is located in regions of the peripheral and central nervous system where pain signaling is mediated,
including the dorsal horn of the spinal cord, PAG, thalamus, and cortical regions associated with central pain
processing, including the anterior cingulate cortex, amygdala and the prefrontal cortex17. CB2 receptor modulation
also decreases pro-inflammatory mediators in a manner that may contribute to antinociceptive effects and improve
endogenous neuroinflammatory properties that play an important role in pain perception18. However, the synergistic
combination of co-administering cannabinoids with opioid agonists has not ever been rigorously evaluated in human
subjects and the degree to which non-human animal results will generalize to human subjects is unknown. The only
Phase I study, of which we are aware, evaluating this concept reported that patients who received 10-20mg of
dronabinol with their stable and normally prescribed dose of opioids experienced decreased pain intensity and
increased satisfaction relative to placebo19. A Phase II study found that titrated dronabinol in chronic pain patients
receiving a stable dose of opioids conferred significant pain relief, reduced secondary problems associated with pain,
and increased ratings on a self-report satisfaction scale (0-10) compared to baseline19.
QST measurement of pain: Chronic pain is conceptualized as a disease of the nervous system that involves
varying degrees of peripheral input and dysregulation of central nociceptive modulatory systems20;21, which are
frequently assessed with laboratory measures. Due to the potential confounding of disease-specific factors, such as
severity and duration, differences in pain management and systemic inequalities, as well as the potential issue of
opioid-induced hyperalgesia, systematic quantitative sensory testing (QST, in which the noxious stimuli are
rigorously calibrated and standardized) in healthy individuals is of great value to elucidate sensory characteristics22-25.
Human experimental pain models link animal and clinical pain studies, and has specifically been recommended for
testing analgesic compounds, and noted as “ideally suited” in proof-of-concept and dose finding studies26. These
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experimental designs allow for precise control over the nature of the noxious stimuli applied to the nervous system
and are crucial in examining and understanding the underlying mechanisms that account for physiological pain
sensitivity and pain perception in clinical pain reports. That is, physically identical stimuli can be applied to all
subjects, permitting the study of drug effects in the experience of pain and minimizing confounding by individual
differences in the noxious stimuli that produce the pain experience. Such variability in psychophysical pain responses
strongly parallels the variability in clinical pain in many samples27-32 (i.e., subjects who are most pain-sensitive in the
laboratory also report the most intense or frequent clinical pain). The use of QST to evaluate drug effects on pain
responses is well-established, sensitive and frequently used in mechanistic studies33-35. A number of studies have
shown strong cross-sectional associations between QST and clinical pain responses in healthy29;36-38 and chronic pain
patients39-43. More importantly, many studies have shown that QST responses predict post-surgical pain44-48 and
treatment outcomes49;50 as well as correlate with changes in clinical pain51-54. QST is also predictive of opioid
analgesia55-60, and opioid dose consistently correlates with multiple QST measures in chronic pain patients61;62. In
addition, basal opioid receptor binding is significantly associated with QST63. Elevated pain sensitivity profiles,
established using QST, is also observed in chronic pain patients at risk for opioid misuse64. Importantly, both static
(measures including threshold and tolerance) and dynamic (methods that probe central pain systems) QST are
responsive to the influences of analgesics59;65;66 and are frequently used to determine analgesic efficacy35;67.
Hydromorphone, which is identified in the current application, specifically produces potent and dose-dependent
analgesic effects on pain reported during QST68 and significantly suppresses secondary hyperalgesia and acute
thermal nociception69. As shown in our preliminary studies, we are experienced in quantifying opioid effects on QST
using these methods (see Figure 1). We do not know of any studies that have used QST to rigorously evaluate
cannabinoid-induced analgesia.
Conclusion: This study is a companion study to IRB protocol 00097937, which was the 1st human laboratory
study to evaluate combinations of cannabinoids and opioids on a comprehensive and validated quantitative sensory
testing battery. This study will further advance this area by examining a second cannabinoid, cannabidiol, which has
significant public health interest due to relative lack of abuse potential. Results of this study will further identify
whether a signal for this medication combination exists that should be advanced into randomized controlled trial
evaluations with clinical pain populations. This study will also assess aspects that would impact drug development
(abuse liability, neurocognitive impairment) and the effect of participant sex on outcomes. The ultimate goal of this
research will be to determine which medication/dose combinations may exert strong analgesic effects, while
minimizing abuse liability and cognitive deficits, in order to advance these medications into clinical trials for the
treatment of chronic pain.
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).
Project Overview: This study will enroll 50 healthy adults, and will aim to complete 30 (15 men, 15 women)
participants. Participants will conduct a within-subject evaluation of the degree to which the FDA-approved
cannabinoid cannabidiol (Epidiolex) enhances the analgesic effect of the prototypic opioid hydromorphone
(Dilaudid). Subjects will complete a Screening visit to establish study eligibility and 5 experimental sessions.
Experimental sessions will occur approximately once weekly and will permit subjects to admit themselves into the
clinical research unit the night before the session if interested. Subjects will be provided with taxi service to and from
the session. Subjects will receive a dose of hydromorphone (4mg, oral) and a double-blind oral dose of study drug or
placebo the morning of each experimental session, and will undergo QST measures of laboratory evoked pain,
provide self-report ratings of drug effects, and complete a neurocognitive battery. The order of sessions will be
randomized with the exception of Session 1, which will always be active hydromorphone + placebo to ensure the
participant has a safe response to hydromorphone before proceeding into the remaining sessions.
Subject Recruitment: Subjects will be recruited from the greater Baltimore area using established recruiting resources
and media advertising, including newspaper, radio, and website listings. All interested individuals will first complete
a phone screen to establish initial study eligibility and individuals who pass will be invited for an in-person screening
during which final study eligibility will be determined.
Screening Visit: Subjects will complete a brief phone screen to determine initial eligibility and will be invited to
complete an in-clinic or remote screen. Subjects will review and sign an informed consent document with a study
staff member to begin the Screening visit. Subjects will provide a urine sample that must test negative for illicit drugs
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and pregnancy (for females), and will then complete a battery of measures to establish study eligibility. Medical
eligibility will be determined by medical staff and will consist of an ECG, a blood sample to analyze hepatic,
hematologic, and chemistry functioning, and a medical history and physical, which will occur prior to any drug
administration. A sample will also be collected to determine P450 CYP 2D6 and 3A4 genotype, to help characterize
drug effects during the data analyses phase.
Experimental Sessions: Upon final eligibility confirmation, subjects will complete 5 experimental study sessions.
The sessions will be conducted on a closed research unit and subjects will be permitted to stay the night before the
session on a clinical research unit. We have chosen to not conduct the entire study using a continuous inpatient
design because we want to impose a minimum 7-day wash-out period between opioid exposures so that any acute
tolerance that may have developed to the hydromorphone dose has time to dissipate and so that cannabidiol, which
has a half-life of 8 hours, has sufficient time to be excreted between drug administrations.
Subjects may either arrive at the BPRU in the early evening prior to an experimental session or the morning
of the session. They will be required to provide a urine sample that tests negative for illicit drugs and pregnancy prior
to admission. Female subjects will be asked to provide a blood sample that will be tested for progesterone, which will
serve as an index of menstrual cycle status. Progesterone analysis is a rigorous method for assessing hormonal cycle
that will enable us to statistically control for the influence of hormone status on QST and response to medications.
Subjects will then be admitted to the research unit.
The morning of each experimental session, the subject will receive a calorie-controlled breakfast each
morning. Following breakfast, subjects will complete a baseline rating of QST and self-report measures (from which
all subsequent ratings will be compared for data analysis purposes). An oral capsule containing either study drug or
placebo will then be administered and hydromorphone (4mg oral in four sessions and a placebo oral dose in one
session) will be administered. The time of drug administration will be selected to enable both cannabidiol and
hydromorphone to exert peak effects at the same time. Subjects will complete QST (see below) and self-report
measures at regular intervals following study drug administration. Self-report measures will include specific opioid
agonist and antagonist effects, to assess whether cannabinoids are exerting an effect on a particular category of
opioid agonist symptom, and will capture whether any negative effects (e.g., nausea) occur as a function of the
cannabinoid dose. Frequent collection will enable evaluation of time to peak drug effects, duration of effects, and
general time course of effects and is a widely used and accepted approach in laboratory studies of drug effects.
During the final assessment each day, subjects will complete a Drug vs. Money Questionnaire to indicate the dollar
value they would place upon the drugs received98. This is a well-accepted proxy measure of abuse liability.
Participants will also receive a brief questionnaire the morning after the study to complete. This is general practice
for the assessment of drug abuse potential and will allow us to examine the full experience of the study drug. Study
staff will document adverse events throughout the study and any subject who experiences a strongly unpleasant effect
of the medications will be able to end participation. Any subject who is experiencing strong agonist effects at the end
of the session will be provided overnight accommodation in the CRU; based on our experience we expect this to a
rare occurrence. Any participant who needs to reside in the CRU will be tested for Covid-19 test before they are
transitioned from BPRU to the CRU.
Quantitative Sensory Testing (QST) Measures of Laboratory Evoked Pain: Subjects will complete a state-of-the-art
quantitative sensory testing (QST) battery, which will comprehensively and systematically measure pain sensitivity.
This approach will provide information regarding the full range of analgesic effects possible, across a wide variety of
psycho-physiologically-mediated, experimentally-induced measures of pain perception. Subjects will complete a
baseline QST session prior to study drug administration on each experimental session day, and will complete the pain
testing battery at regular intervals during the experimental session day. Each administration of the QST battery will
take 20-30 minutes. The QST battery will consist of threshold and tolerance, temporal summation, and conditioned
pain modulation (CPM) tests. The threshold responses will be conducted in randomized and counter-balanced order,
and conditioned pain modulation will always occur last.
Threshold Responses will be assessed using thermal and pressure stimulation. Thermal threshold: All
contact heat stimuli will be delivered using a peltier-element-based stimulator (Medoc, Israel). Two trials of heat pain
threshold will be administered using an ascending method of limits paradigm. The thermode will gradually increase
in temperature (rate of rise = .5oC/sec) from a pre-set baseline (31oC), until the subject indicates when the stimulus
“first feels painful” (threshold, HPTh) and presses a button (which terminates the procedure) indicating that the pain
is intolerable (tolerance, HPTo). Pressure threshold: A pressure algometer will be utilized to assess responses to
pressure stimulation at a variety of anatomical sites in a randomly determined order. The pressure algometer
(Somedic; Sweden) uses a rubber probe covered with 1mm polypropylene material; pressure at the site is gradually
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increased at a steady rate. Subjects indicate when the stimulus is first perceived as painful, which terminates the
application. The algometer produces a sensation of localized pressure; technicians will place the probe of the
algometer in the center of each muscle group or anatomic site when delivering the mechanical stimuli. Thirty-second
inter-stimulus intervals will be maintained for all stimuli. Each trial will be averaged together to result in one HPTh,
HPTo, and PPTh measure.
Temporal Summation (TS) of Pain will be assessed in 2 ways, using repetitive thermal stimuli and repetitive
punctuate stimuli. Sequences of 10 heat pulses will be applied using the Medoc. (Note: within each 10-pulse
sequence, the temperature of each phasic stimulus is the same). Within each sequence, successive thermal pulses at a
given temperature will be delivered for a duration of approximately 0.5 sec each, with an approximately 2.5-sec
inter-pulse interval. Subjects will verbally rate the perceived intensity of each thermal pulse on a 0-100 rating scale
and may terminate the procedure at any time. Windup is measured as the differences between the highest rated
thermal stimulus and the 1st thermal stimulus.99
Mechanical Temporal Summation will be studied using punctate stimulators (a set of weighted pinprick
stimulators with fixed stimulus intensities (flat contact area of 0.2 mm diameter) that exert forces of 8- 512 mN). The
probes are applied perpendicular to the skin. We will apply both single stimuli and 10-stimulus trains at 1HZ, and
will record the subjects pain rating (0-100). Single pinprick stimuli are alternated with the trains of 10 stimuli. The
mean pain rating of 10-stimulus trains divided by the mean pain rating to single stimuli is then calculated as a
ratio.100
Cold Pressor Testing and CPM: A series of procedures designed to elicit and measure endogenous inhibition
of pain will be applied. In the present protocol, subjects will undergo a series of cold pressor tasks (i.e., the
conditioning stimuli) consisting of immersion of the hand for up to 1 minute in a circulating cold water bath. During
hand immersion, pressure responses or temporal summation will be re-assessed while subjects’ hands remain in the
cold water. Subjects may remove their hand at any time. Two minutes after finishing the first immersion, subjects
will re-immerse their hand in the water, and one of these tests will be re-assessed, each separated by 2 min and
identical to the first 2 trials (the tests will be conducted in random order). A CPM Index is quantified as the average
percent change (across trials) in PPTh or TS during the cold pressor tasks relative to baseline ratings [(PPTh or TS
during cold pressor/PPTh or TS prior to cold pressor)*100.101 One final cold-water immersion will be performed at
the conclusion of the CPM procedures. This will involve a typical cold pressor task, using immersion of the hand
until the subject’s tolerance is reached, with a 5-minute uninformed time limit.
Capsaicin: Capsaicin sensitization procedures similar to well established protocols developed by Peterson
and colleagues will be utilzed70. Heat will be delivered using, a computer driven, peltier device, heating element
(Medoc TSA II). The procedure involves a 35 minute sensitization period (conducted during the baseline period)
with a 1.25inch2 treatment site on the non-dominant, ventral forearm. The thermode will be heated to 45°C for 5
minutes and pain ratings will be collected every one minute on the 0-100 rating scale. An open square raised
adhesive frame (internal dimensions same as thermode, to reduce leakage beyond the site) will then be applied and
capsaicin cream (10%)71 will be spread onto the skin and permitted to absorb for 30 minutes. This induces mild-
moderate (48.25+27.93), but well tolerated pain. Capsaicin is then removed and the heat pain threshold and
mechanical temporal summation (described above) will be conducted again in the area. The treated skin will be re-
kindled for each of the additional QST sessions each session by heating the treatment site with the thermode at 40°C
for 5 min. Following each rekindling episode, heat pain threshold and mechanical temporal summation as well as
measurement of secondary hyperalgesia will be conducted. The area of secondary hyperalgesia will be quantified
with a von Frey hair by stimulating along eight linear paths around the treated site. Stimulation starts well outside the
hyperalgesic area, and continues towards the treated skin area until the subject reports a change in sensation. The
border is marked on the skin with a pen and traced to acetate paper, which is subsequently measured. Studies have
demonstrated excellent test-retest stability in 2o hyperalgesia measurements over rekindlings72;73;73 and the procedure
is ideal for including in paradigms with repeated testing as the rekindlings allow for rapid evaluation of capsaicin
sensitization (which typically necessitates at least 30min each).
Additional Study Measures: Study measures comprise both pharmacologically and qualitatively nonspecific
measures (e.g., any drug effect) and qualitatively specific measures (e.g., liking, good effects, bad effects), that are
considered the gold standard method by consensus panels and the FDA for detecting drug effects (Comer et al., 2012).
We will also conduct comprehensive neurocognitive testing, using a standard battery that is regularly used by our
group at BPRU in studies assessing both opioid and cannabinoid effects.
Study Measures to Establish Eligibility and Characterize Sample:
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·
 BPRU Demographic Questionnaire: A questionnaire designed by us to document standardized demographic
items (e.g., age, gender, marital status).
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 Alcohol/Drug subscale of the Addiction Severity Index: A 31-question subscale to 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-5 dependence on alcohol and/or drugs.
·
 Brief Pain Inventory (BPI): 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.
·
 Fagerström Test for Nicotine Dependence (FTND): A 6-item measure to determine presence of smoking and
severity of nicotine dependence.
·
Beck Depression Inventory (BDI): The BDI-II is a 21-item self-report measure of depressive symptoms.
·
Beck Anxiety Inventory (BAI): The BAI is a 14-self-report measure of anxiety symptoms.
·
 Barratt Impulsiveness Scale: 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): A 20-item self-report measure to characterize positive and
negative emotional responses to pain.
·
 Pain Catastrophizing Scale (PCS): A 14-item self-report measure to characterize the emotional response to pain,
with particular emphasis on anxiety and/or fear of pain.
·
PROMIS Global Health Scale: A 10 item-self report measure of quality of life.
·
Distress Tolerance Scale: A 15-item self-report measure of tolerance to distressing situations.
·
Discomfort Intolerance Scale: A 7-item self-report measure of tolerance to distressing situations.
Session Measures:
·
Clinical Opiate Withdrawal Scale: 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 subjective reports of drug effects items on a scale of 0
(none at all) to 100 (strongest possible), including items such as 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.
·
Next Day Questionnaire: The next day questionnaire is a standard practice for capturing abuse potential of a
drug. It is composed of a small subset of questions from the session scales.
Cognitive/Motor Tests:
·
 Divided Attention Task (DAT): Participants simultaneously perform two different simple tasks based on visual
stimuli presented on a computer screen. This task is computer based.
·
Digit Symbol Substitution Task (DSST): Participants must hand type patterns presented to them on a computer
screen for 90 seconds
·
 Paced Auditory Serial Addition Task (PASAT): Participants are provided a string of single digit numbers on the
computer and must add the total of the prior to integers presented and respond by selecting the answer using the
computer mouse on the screen.
·
 Circular Lights: Participants will be asked to follow a series of lights on a circular lights device and the outcome
will provide a measure of motor accuracy.
Participants will also be asked to provide an optional blood sample that will be banked with the Genetic Resources
Core Facility. Samples will be analyzed at a later date and governed by a separate hypothesis-driven IRB protocol.
Genetic sample collection will be optional and will not impact primary study eligibility.
Optional Hair Analysis Substudy: Participants will be asked whether they would like to participate in a hair
sampling substudy. The study will be considered optional to prevent disinterest in hair sampling from negatively
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impacting recruitment for the primary study. The rationale for this substudy is that hair analyses are emerging as an
important method for detecting drugs use. This study can contribute valuable information to efforts to refine hair
analyses because it administers drugs that have known abuse potential in a controlled manner and at known and
uniform dose levels. The study PI has been asked by a NIDA Program Officer to collect hair samples from willing
participants to be analyzed by the Neuroproteomics and Neurometabolomics Center at Northwestern University.
Samples will be used to improve Maldi Sampling Techniques, to determine the degree to which accurate
identification and quantification of levels of opioid and cannabinoid exposure in hair samples from individuals who
are biologically confirmed to have no extra-study drug use is possible. Participants who are enrolled in the parent
study will be asked about interest in this substudy and consented into the substudy via an oral consent procedure. The
substudy will collect a hair sample at the beginning and end of the 6-week participation period. Samples will be
collected via the commercially available Hair Test Collection Kit from Therapak and coded by participant ID
numbers so that no PHI will be shared with the Center. Samples will be sent annually to the Center for analyses.
b. Study duration and number of study visits required of research participants.
Participants will complete a Screening visit and 5 experimental session visits. Though sessions are expected to occur
once weekly (for 5 weeks) participants will be able to extend sessions to greater than once per week if necessary, to
accommodate potential scheduling barriers.
c. Blinding, including justification for blinding or not blinding the trial, if applicable.
Participants and staff will be blinded to the doses of study medications being administered at each study visit. This
will allow a rigorous test of the study hypotheses by not biasing participants or staff towards differential pain ratings.
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.
We have included placebo control conditions for each study drug, to assist with interpretation of the study results.
Since this study will recruit healthy individuals and we will not be removing access to a known treatment, we believe
that inclusion of the placebo conditions poses low risk to participants.
f.
Definition of treatment failure or participant removal criteria.
Participants will be removed from the study if they remove their consent to participate, become pregnant, refuse to
adhere to the study session schedule, or if it becomes clear that their continued participation could put them at
increased risk (e.g., develop a chronic pain condition that requires treatment, onset of a medical/psychiatric disorder).
These decisions will be made in conjunction with the BPRU medical team.
g. Description of what happens to participants receiving therapy when study ends or if a participant’s
participation in the study ends prematurely.
N/A
5.
Inclusion/Exclusion Criteria
Inclusion Criteria:
·
Aged 18-75
·
Urine sample tests negative for common illicit substances of abuse, including cannabis
·
Medically cleared to take study medications
·
Are not pregnant or breast feeding
·
Willing to comply with the study protocol.
Exclusion Criteria:
·
Meet DSM-5 criteria for alcohol/substance use disorder
·
Taking opioids for pain
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(IRB00097937; IRB00125605) and we have evidence that it
1
4mg
0mg (placebo)
Randomized
2
4mg
50mg
3
4mg
100mg
4
4mg
200mg
Session (type/day)
screening day. Sessions 2-5 will be counterbalanced
and randomized across participants.
·
Previous adverse reaction to a cannabinoid product
·
Prescribed and taking stimulants or benzodiazepines
·
Answer “yes” to item 1 of the Brief Pain Inventory indicating chronic pain
·
Self-report any illicit drug or cannabinoid use in the past 7 days
·
Presence of any clinically significant medical/psychiatric illness judged by the investigators to put subject at
elevated risk for experiencing an adverse event
·
History of seizure disorder
·
Have a known allergy to the study medications or sesame seed oil
·
ALT or AST levels >3x ULN and/or Bilirubin levels >2x ULN during Screening
·
Current (past 60-day) suicidal thoughts or past year history of suicidal behavior
·
Taking medications contraindicated with hydromorphone or cannabidiol
·
Have a history of clinically significant cardiac arrhythmias or vasopastic disease
·
Have an abnormal and clinically-significant ECG
6.
Drugs/ Substances/ Devices
a. The rationale for choosing the drug and dose or for choosing the device to be used.
Study Drugs: Hydromorphone and cannabidiol will be over-encapsulated by our research pharmacy and administered
orally.
Hydromorphone (Dialudid) is a potent mu-opioid agonist that we
Table 1. Study Drug Doses
have extensive experience administering in controlled laboratory
Hydromorphone
Cannabidiol
settings. Hydromorphone is not subject to differences in CYP                                                    (oral)                      (oral)
metabolic enzymes (in contrast to other opioids such as oxycodone)
Nonrandomized
and therefore will not require us to screen out individuals with
recent exposure to CYP inhibitors/inducers, or to
analyze/statistically control for CYP metabolic profiles. We have
selected a 4mg oral hydromorphone dose for this study because it is
the dose being administered in our companion studies
5
0mg (placebo)
0mg (placebo)
produces a mild-moderate effect (versus a ceiling or floor effect)           Session 1 will be nonrandomized and used as a safety
and will therefore allow us to visualize changes as a function of the
cannabidiol. 4mg oral hydromorphone is also a dose that is
commercially available and regularly prescribed for analgesia, which increases the clinical relevance of this study.
Based on clinical experience, we expect it to produce a moderate analgesic effect on pain. This is an important
feature because too strong a dose could overwhelm the cannabinoid effect and prevent us from effectively evaluating
the study hypotheses. A moderate dose of hydromorphone will better enable us to evaluate shifts in the analgesic
curve as a function of the study drug, and provide a stronger assessment of whether cannabinoids will enhance the
analgesic effect of hydromorphone.
Cannabidiol (Epidiolex) has been strategically chosen for this study because it is a widely-used, commercially-
available Schedule V cannabinoid medication that is currently indicated for seizure control in persons with Lennox-
Gastaut syndrome and severe infantile myoclonic epilepsy, but which could be prescribed off-label for the adjunctive
treatment of clinical pain. Epidiolex is the only FDA-approved formulation of cannabidiol and we are
proposing to administer it in doses of 50mg, 100mg, and 200mg. Epidiolex has been administered safely to
humans in doses up to 4500mg(133). This dose range was selected to be consistent with those reported by a recent
review of Epidiolex dose levels in clinical populations (145) and we prioritized doses on the lower end of the spectrum
to better visualize an opioid-enhancement effect (versus producing a strong cannabidiol-specific effect). Epidiolexis
an oral solution that will be purchased commercially, the BPRU pharmacy will prepare the dose and a flavor-matched
control for placebo dosing. A recent pharmacokinetic study reported that a 200mg dose of Epidiolex, administered
orally, reached peak concentrations in 2-3 hours and had a half-life of 8-9 hours. It is highly lipophilic and subject to
extensive first-pass metabolism via the CYP 1A1, 2D6, and 2C9 pathways, which yields an active metabolite (7-OH-
CBD). 7-OH-CBD is believed to contribute to cannabidiol’s efficacy for seizure control and has a half-life of 13.3
hours, with no evidence of psychoactive effects(143).
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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: 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 4mg oral hydromorphone for the study sessions because we have ongoing
experience with this dose in another IRB approved study (PI Dunn, IRB_00047423) and we have observed that it
produces the effect intended for investigation in this study; namely, that it produces a mild-moderate effect that will
better position this study to evaluate whether cannabidiol can increase or decrease drug effects.
Hydromorphone was strategically selected for this study as the exemplar opioid for this study because it is
not subject to differences in CYP metabolic enzymes and therefore will not require us to screen out individuals with
recent exposure to CYP inhibiting or inducing medications, or to analyze and statistically control for CYP metabolic
profiles in individual subjects. Further, in contrast to morphine, hydromorphone also does not produce a localized
adverse effect when administered IM. Both doses of hydromorphone are within the range that is commercially
available, which increases the clinical relevance and direct application of these study results into clinical practice,
and our data indicates 4mg oral hydromorphone will produce a moderate analgesic effect following pain testing. This
is an important feature because too strong a dose of an opioid analgesic could overwhelm the cannabinoid effect and
prevent us from effectively evaluating the study hypotheses. By selecting a dose of hydromorphone that produces a
moderate effect, we will be able to evaluate shifts in the analgesic curve that occur as a function of cannabidiol,
which will allow us to better determine the degree to which cannabidiol can augment the analgesic effect of
hydromorphone. There is also no apparent effect of gender on the pharmacokinetics of hydromorphone.
We have selected hydromorphone for this study because it is a prototypical opioid with a known safety
profile and because we have extensive experience administering this drug in oral preparations. We have selected a
mid-level dose because it is within the range of doses approved by the FDA. It is also sensitive to the QST tests we
have proposed, and we therefore believe it will provide an ideal opportunity to evaluate whether the curve of
hydromorphone is shifted as a function of cannabidiol administration.
Cannabidiol: Cannabidiol is a constituent of the cannabis plant that is being actively investigated for efficacy in a
wide range of potential indications (including anxiety and alcohol/substance use disorders, as evidenced by
clinicaltrials.gov entries) because of its unique pharmacological mechanisms of action. Specifically, it acts as an
inverse agonist on the cannabinoid CB1 and CB2, as a 5-HT1a agonist, as a positive modulator of the transient
receptor vallinoid-1 (TRPV1) receptor, and as an allosteric modulator of the mu and delta opioid receptors (137, 142).
We have proposed to examine cannabidiol in this study because of evidence from preclinical studies that it may
meaningfully shift the opioid-analgesic curve, and because it has good safety profile that suggests it may have real
potential for being widely used in real-world settings. Specifically, there is substantial preclinical evidence that
cannabidiol may interact meaningfully with opioids (134-136) and the only empirical human studies on this topic have
reported that cannabidiol doses of 400 and 800mg can be safely coadministered with the highly potent opioid
fentanyl (138) and can reduce opioid craving in persons with opioid use disorder (139). Despite preclinical evidence that
cannabidiol may enhance antinociception in preclinical rodent models (140-141), this outcome has not yet been
examined in humans. Finally, unlike some other cannabinoids, cannabidiol is believed to be relatively void of
euphoric and psychoactive effects, as evidenced by an abuse liability examination that reported supratherapuetic
doses ranging from 750mg to 4500mg demonstrated little to no signal for abuse potential relative to alprazolam and
dronabinol comparators, and the 750mg dose (more than 3 times the upper dose proposed here) did not differ from
placebo on any measure (133).
Capsaicin: 10% capsaicin topic cream will be applied as part of the standardized quantitative sensory testing battery.
This is a conventional pain testing technique. For application, a piece of thick, non-porous adhesive dressing with a
1.25inch2 opening will be applied to the skin at the location of intended application. The area will be marked with a
pen or sharpie for later visualization. A 0.35g application of 10% capsaicin cream will be applied inside this opening
and evenly spread on the skin. The area will then covered by Tegaderm transparent dressing and the capsaicin cream
will be permitted to absorb into the skin for 30 minutes. Capsaicin will then be removed from the skin using alcohol
prep pads.
c. Justification and safety information if non-FDA approved drugs without an IND will be administered.
N/A
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7.
Study Statistics
a. Primary outcome variable:
·
Primary Aim 1: The primary outcome will be the area under the curve of each QST procedure, which will
provide an assessment of the mean duration and magnitude of the drug effect. Primary outcomes will be tested with
repeated two-factor (Drug Condition x Time) models to examine main and interaction effects for all raw data as
designed. If there is large variation across subjects at the baseline timepoint, the raw data will be transformed as a
change from baseline and analyzed in drug condition by time models. Statistical analyses will be conducted using
multilevel analyses with an autoregressive covariance structure using SAS PROC MIXED Software131. These
analyses will permit an examination for effects of drug condition and time effects associated within the course of the
study. Interpretation of drug condition main effects and interactions will rely on Tukey post-hoc tests. This aim will
also assess frequency of adverse events as a function of study drug.
Specific outcome variables for the QST procedures will be as follows:
a. Heat Pain Threshold and Tolerance: HPTh and HPTo in ºC (both in normal and capsaicin treated skin)
b. Pressure Pain Threshold: PPTh in kilopascals
c. Thermal and Mechanical Temporal Summation: Verbal pain ratings (both in normal and capsaicin treated
skin for MTS)
d. Conditioned Pain Modulation: The index score of CPM:PPTh and CPM:TS (compared to baseline) for each
dose
e. Cold Water Tolerance: Time to tolerance (compared to baseline) for each dose.
· Primary Aim 2: The Drug vs. Money questionnaire will be compared across dose conditions, using peak
monetary rating for each dose as the primary outcome. Within-subject changes, as a function of dose, will be
analyzed using a repeated measures analysis of variance (ANOVA).
· Primary Aim 3: Neurocognitive tests will be compared as a function of study drug dose, using study session
number (1-6) as a covariate to control for practice effects. Specific outcome measures will include:
a. Divided Attention Task (DAT): Accuracy with which they perform the two tasks
b. Digit Symbol Substitution Task (DSST): Accuracy, total number of patterns completed in allotted time
c. Computerized version of the Paced Auditory Serial Addition Task (PASAT): Summed of correct trials
b. Secondary outcome variables.
Demographic and drug use characteristics, including a positive signal (defined as >20 points rating from baseline on
VAS rating of Drug Effect from Session 1), that are hypothesized a priori to be associated with outcomes (e.g., Body
Mass Index) will be compared across sex groups and significant differences will be included as covariates in the
subsequent analyses. All analyses will be repeated and sex (male/female) will be added as a factor to the analyses.
c. Statistical plan including sample size justification and interim data analysis:
This power analysis is based upon a recently published paper that used methods similar to those proposed here and
is the only study published on the effect of combined cannabinoids (dronabinol) and opioids on cold pressor testing
outcomes (144). Sample size estimates were premised with a power of 0.8, alpha =0.05 and calculated effect sizes
(Cohen, 1988). Analyzing cold pressor outcomes of threshold and tolerance, those analyses suggested that a sample
size ranging from 10-15 would be sufficient to detect large effect sizes for Aims 1-3 (Cohen’s d = 1.1-1.4). Aim 4 is
a sex-comparison, for which we plan to double our enrollment levels to support. We are therefore proposing to
enroll 50 participants (25 men, 25 women) in order to achieve 40 study completers (20 men, 20 women). This
number is consistent with the number of participants enrolled in the aforementioned study (n=18), which did not
conduct a between-sex comparison(144).
d. Early stopping rules.
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Not abiding by the BPRU policies and procedures, engaging in behaviors towards staff or other participants that are
abusive, or development of an intercurrent illness or condition (such as pregnancy) that changes the participants risk
may result in medical discharge from the study.
8.
Risks
a. Medical risks, listing all procedures, their major and minor risks and expected frequency.
a. Hydromorphone: 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 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.
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 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 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 throughout the study session, up to 8
hours, by trained staff who will have access to the opioid antagonist naloxone to reverse the opioid agonist effects.
Hydromorphone has no known interactions with cannabidiol.
b. Cannabidiol: Cannabidiol has few contraindications. It should not be administered to persons with known
sensitivity to cannabidiol. Epidiolex is extensively metabolized by the liver, therefore persons with moderate-severe
hepatic impairment (defined in the FDA product label as ALT or AST levels >3x ULN and/or Bilirubin levels >2x
ULN) who might have different plasma concentrations of Epidiolex as a result of liver impairment will also be
excluded. Epidiolex has been reported to produce somnolence or sedation in up to 32% of patients (compared to 11%
of patients receiving placebo) and this may be further exacerbated in persons who are taking other CNS depressants.
The FDA also recommends that persons receiving any antiepileptic drug, of which Epidiolex is one, be screened for
suicidal behaviors prior to beginning drug administration. Additional side effects reported in clinical trial
examinations of Epidiolex for seizure indications in adult and child populations include decreased appetite, diarrhea,
weight decrease, gastroenteritis, lethargy, fatigue/malaise, insomnia, irritability/agitation, drooling, gait disturbance,
rash, hypoxia, and infections. Epidiolex should not be coadministered with other strong CYP3A4 or CYP2C19
inhibitors or inducers, as these will change the plasma levels of cannabidiol. A determination of the safety of
cannabidiol during pregnancy has not yet been made.
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c. Capsaicin: Capsaicin is the main ingredient in hot peppers, and is used as an over the counter drug for the
treatment of pain. The dose of capsaicin we are using is higher than what is available over the counter, although it is
less than half of the dose in a single habanera pepper. Capsaicin does cause pain, like a hot pepper may do when it is
eaten. Capsaicin may produce some local redness and swelling that will disappear within a day. The area of skin
where the capsaicin is applied could be sensitive for up to 48 hours. Capsaicin may cause a burning feeling in the
eyes or other areas of the body if accidentally rubbed onto other skin areas.
d. Chance That Participants May Begin Abusing Opioids or Cannabinoids Following Exposure to Study
Drugs: There is a small but potential risk that exposing non-drug abusing individuals to doses of hydromorphone or
cannabinoids may elicit reinforcing effects that could 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.
e. 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.
f. 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 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.
a. Protection Against Hydromorphone Risks: We 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.
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. Participants will be free
to discontinue study participation at any time without consequence. The dose of hydromorphone that is being
administered is consistent with clinical care, and is a medium level dose for the treatment of pain. Further, The
Qualifying Session provides us a unique opportunity to assess for sensitivity to hydromorphone, and any participant
who shows intolerance to hydromorphone during the Qualifying Session will be excluded from the primary study.
Great care has been taken in selecting the appropriate drug doses to ensure hydromorphone is well-tolerated and safe
for our participants and participants will also be able to discontinue study participation at any time. 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 are administering a mid-level dose and have extensive experience administering
this dose at controlled levels in healthy controls. 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 12 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, then patients are monitored carefully.
Specifically, they will be 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 deemed necessary by the physician. 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. In the unlikely event that a participant who is participating in a BPRU session or being housed at the CRU
requires medical assistance that is outside the scope of what can be provided by the study medical team, the study
team will contact 911 and request ambulance transport to the ER.
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b. Protection Against Cannabidiol Risks: The largest identified risk of cannabidiol is that chronic administration
can lead to elevated liver enzymes. This risk is recognized as being transient and readily reversible, and is unlikely to
happen in the current paradigm because only three acute doses will be administered. An additional risk is that
participants may experience a hypersensitivity to cannabidiol. To mitigate these risks, we will exclude participants
who endorse having previously experienced negative effects to cannabinoid products, or who have moderate-severe
hepatic impairment, as defined by the FDA-approved Epidiolex label. We will also conduct psychiatric screening
during the Screening session to ensure that patients with current or history of psychiatric events are excluded from
study participation. Further, all participants will be informed about the potential side effects of the study medications
and will be permitted to end study participation at any time if they experience negative events, with no consequences.
To protect against any persistent drug effects, we are providing participants with taxi service to and from the study
sessions and are budgeting for participants to stay the night at the CRU following study drug exposure if necessary.
Based on our previous experience, we expect this to be a rare occurrence but are prepared to make that option
available as needed.
c. Protection Against Risks That Participants May Begin Abusing Opioids or Cannabinoids Following
Exposure to Study Drugs: 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
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 assessment126. 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 outcomes127. Third, a recent study concluded that investigational administration of intravenous
cocaine to intravenous inexperienced cocaine users did not increase the risk of recreational intravenous use128.
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-
up129. 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 treat130. Overall, given the substantial data available in the literature
and our own laboratory experience, we feel confident that administration of small quantities of psychoactive drugs to
individuals with recreational histories of drug abuse will not be associated with future drug use behavior.
Participants will also not be informed about the specific medication they are receiving, which is a common
procedure used by our research unit to minimize bias in responding. This procedure also makes it difficult for the
participant to seek out drugs they may have found reinforcing during the study session, thus further minimizing the
opportunity for study participation to increase risk of non-study drug abuse.
d. Protection Against Risks of 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 standardized pain tests that
are known to produce short-lived effects and thus are unlikely to produce any residual pain. Third, the measures rely
on the participant ending the pain testing procedure as an outcome measure, which means that all participants are
encouraged to remove themselves from the painful stimulus at any time and that they are in control of the magnitude
and duration of pain they experience. 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 presser 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
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participants will be monitored 24 hours by study staff and will have access to medical care and concomitant
medications to treat residual pain if necessary. We will also document and review all adverse events reported from
the pain testing session and will follow any recommendations they may have regarding the cessation of pain testing.
e. Specific Protection Against Risks with Capsaicin: Capsaicin is being used to induce mild pain/discomfort and is
a primary outcome of the study. We will ensure that all participants are informed about the discomfort associated
with capsaicin so they may make an informed decision regarding their study participation. One of the primary risks
of capsaicin is that it could be accidentally transferred to another part of the body. To prevent this from happening,
we will make sure the exposure site is well-marked and that all residual topical cream is removed with alcohol pads
once the cream has been mostly absorbed. We will also be able to apply ice to the exposure site to reduce any
persistent discomfort associated with capsaicin.
f. Protection Against Risks Associated with Breach of 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. 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. It is possible that participants’ urine samples may test positive for the study drugs for up to 1
week after each session. To mitigate any potential negative impact this may have on participants, we will inform
them of this potential risk in the ICF so they may make an informed decision regarding their participation despite this
potential consequence, and will provide any interested participants (who sign a release of information) with a letter
signed from the study investigator stating that their urine sample may be positive for drugs that can be considered
abusable for up to 7 days following a study session.
e. Financial risks to the participants.
None.
9.
Benefits
a.
Description of the probable benefits for the participant and for society.
There is no direct benefit of this study to the participant. However, this study will provide the first empirical evidence
in humans of the magnitude and duration by which cannabinoids may enhance opioid analgesic effects, using a
standardized quantitative sensory testing (comprehensive pain testing) battery. This information will advance the use
of cannabinoids from treatment-refractory conditions to more wide-spread use for pain treatment. A positive result
will provide new medication targets and will help lead efforts to reduce societal reliance upon opioids for the
treatment of pain. Reduced availability of opioids will lead to reductions in use/abuse and related problems (risky
injection behavior, opioid overdose).
10.
Payment and Remuneration
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a.
Detail compensation for participants including possible total compensation, proposed bonus, and any
proposed reductions or penalties for not completing the protocol.
Participants will receive $30 for the Screening Visit, and will receive payments in an escalating fashion to promote
study retention. Specifically, participants will earn $150/Session 1, $200/Session 2, $250/Session 3, $300/Session 4,
and $350/Session 5. Total possibly study-related earnings will be $1,280.
Participants will be offered $25 for each hair sample provided, for a total of $50 for the optional substudy.
11.
Costs
a.
Detail costs of study procedure(s) or drug (s) or substance(s) to participants and identify who will
pay for them.
All study related procedures will be paid by a National Institute on Drug Abuse grant; participants will not incur any
direct cost for study participation.
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Kaufman MJ, Levin JM, Kukes TJ, Villafuerte RA, Hennen J, Lukas SE, Mendelson JH, Renshaw PF. Illicit cocaine use patterns in
intravenous-naive cocaine users following investigational intravenous cocaine administration. Drug and alcohol dependence. 2000 Feb 1;
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Bigelow GE, Brooner RK, Walsh SL, Preston KL, Liebson IA. Community outcomes following research exposure to cocaine or
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Printing Office; 1995. p. 354.
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College on Problems of Drug Dependence. Human subject issues in drug abuse research. Drug and Alcohol Dependence. 1995; 37(2):
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131. Singer JD. Using SAS PROC MIXED to fit multilevel models, hierarchical models, and individual growth models. J Educ Behav Stat.
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132. Jicha, C.J., Lofwall, M.R., Nuzzo, P.A., Babalonis, S., Elayi, S.C., & Walsh, S.L. (2015). Safety of oral dronabinol during opioid
withdrawal in humans. Drug and Alcohol Dependence, Vol. 157, pp 179-183.
133. Schoedel. K.A., Szeto, I., Setnik, B., Sellers, E.M., Levy-Cooperman, N., Mills, C., Etges, T., and Sommerville, K. (2018). Abuse
potential assessment of cannabidiol (CBD) in recreational polydrug users: A randomized double-blind controlled trial. Epilepsy & Behavior,
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134. Markos, J.R., Harris, H.W., Gul, W., ElSohly, M.A., & Sufka, K.J. (2018). Effects of cannabidiol on morphine conditioned place
preference in mice. Planta Med, Vol. 84 (4), pp 221-224.
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140. Rodríguez-Muñoz, M., Onetti, Y., Cortés-Montero, E., Garzón, J., & Sánchez-Blázquez, P. (2018). Cannabidiol enhances morphine
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(2014). Cannabidiol and endogenous opioid peptide-mediated mechanisms modulate antinociception induced by transcutaneous
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clinical populations. British Journal of Clinical Pharmacology.In press.
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ICF_001.pdf: 
Evaluating Cannabidiol (CBD) to Enhance the 
Analgesic Effect of Hydromorphone in Humans   
 
NCT: 04036968 
 
Informed Consent Date: November 1, 2021 
 


 
Approved November 1, 2021 
Date: November 1, 2021 
Principal Investigator: Kelly Dunn, Ph.D. 
Application No.: IRB00214289 
 
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Combined Parental Permission/Informed Consent/Authorization December 2018 Version 16 
 
 
 
 
 
 
 
 
 RESEARCH PARTICIPANT INFORMED CONSENT AND PRIVACY 
AUTHORIZATION FORM 
 
Protocol Title:  
 
Enhancing Medication-based Analgesia in Humans- Study 2 
 
Application No.:   
IRB00214289 
 
Sponsor/Supporter/Funded By: National Institute on Drug Abuse 
 
Principal Investigator: Kelly Dunn, Ph.D.,  
5510 Nathan Shock Dr, Baltimore MD 21224.  
P: 410-550-2254, F: 410-550-0030, Email: kdunn9@jhmi.edu 
 
 
You are being asked to join a research study. Participation in this study is voluntary. Even if you decide 
to join now, you can change your mind later. 
 
1. 
Research Summary (Key Information): 
The information in this section is intended to be an introduction to the study only.  Complete details of 
the study are listed in the sections below. If you are considering participation in the study, the entire 
document should be discussed with you before you make your final decision.  You can ask questions 
about the study now and at any time in the future. 
 
This research is being done to evaluate whether combining two medications is an effective way to treat 
pain.   
 
The study consists of an eligibility Screening period and 5 study sessions that are scheduled 
approximately 1 week apart. Each study session will last an entire day (around 8 hours). At the 
beginning of each study session you will receive 2 blinded study medications. The medications are all 
FDA-approved medications but are being given for non-FDA approved reasons as part of this study and 
may be from any of the following categories: a prescription stimulant, a prescription cannabinoid 
(related to the active ingredient in cannabis or marijuana), 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 will know what combination of 
medications you have received.  
 
Throughout each session, we will collect information about how the study medications make you feel 
and whether they help reduce pain. We will measure their ability to reduce pain by conducting some 
pain testing procedures with you in our laboratory. These procedures are commonly used by laboratories 
throughout the world and include the application of a topical cream and we describe them in more detail 
for you later in this form.  
If appropriate for this study, a scanned copy of 
the signed consent form should be uploaded to 
the participant’s Epic/EMR record. 
 
 
 
 
Patient I.D. plate 


 
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If you decide to participate in this study, the main risks will be related to taking the study medications 
and the pain testing procedure. Even though you won’t know exactly what medications you are 
receiving, we describe the effects you might experience in detail for you later in this form so that you 
can make an informed decision about whether you want to participate. Some risks could be serious.  In 
addition, even though the pain testing procedure may produce some level of pain, we expect the pain to 
be relatively mild, and you will be in charge of how much pain you experience because you can chose to 
end the procedure at any time (with no study-related consequences).  
 
You can decide to participate now and change your mind later with no consequences.  
 
There will be no personal benefit to you from study participation, but your participation, and the 
knowledge gained, may benefit others in the future. 
 
2. 
Why is this research being done? 
This research is being done to evaluate whether combining two medications is an effective way to treat 
pain.   
 
Are there any investigational drugs/devices/procedures? 
This study will provide you with two medications to swallow at the beginning of every study session. 
All the medications that are being administered in this study are approved by the U.S. Food and Drug 
Administration (FDA), however their use in this study is investigational because we are using them in a 
way that the FDA has not yet approved. The FDA is allowing the use of these study medications for this 
study. 
 
The medications that may be tested in this study include prescription stimulants, prescription 
cannabinoids (related to the active ingredient in cannabis or marijuana), benzodiazepines (e.g., anti-
anxiety medication), prescription opioids (e.g., a pain medication), over-the-counter medications, or 
placebo (contains no medication, like a sugar pill). 
 
Who can join this study? 
People with who are between 18 years and 75 years old and healthy may join 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: 
 
Study Screening:  
The goal of the study Screening is to make sure that you are eligible for the study and healthy, so that 
participating in this study will not put you at risk. Part of this Screening process may be conducted 
remotely. 
 
As part of your Screening, 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 and to help us understand your response to the study medications.  You will also complete an 
electrocardiogram (ECG) to make sure your heart is healthy.  
 
Prior to beginning your 1st study session (see below) you will also meet with a medical staff member to 
complete a brief history and physical.   
 
 


 
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Study Sessions:   
If you are determined to be eligible after completing our study Screening visit then you will be asked to 
complete 5 study sessions. Each session will last all day (around 8 hours). You are welcome to spend the 
night before each session in our clinical research unit, which is located on our same hospital campus. If 
you prefer not to spend the night, you may arrive the morning of the session. However, since we cannot 
be sure how you will feel after taking the study medications, we will ask you to not drive to the sessions 
and will pay for a taxi to bring you to and from the sessions if needed.  
 
Before we begin each session, we will collect a urine sample that will be tested for recent drug use. If 
you are female, we will also test you for pregnancy and will collect a blood sample (no more than 2 
tablespoons) from you that we will test to determine your hormone status. It is possible that the staff 
member may cancel your study session if your urine results indicate recent drug use or pregnancy. If 
your study session is canceled, you will not receive payment for that visit and will have to reschedule 
your session for another day.  
 
We will work with you to ensure you have a calorie-controlled breakfast prior to your session beginning. 
Study sessions are expected to last all day. During the session you will first be asked to complete some 
questionnaires that ask you about how you feel and to complete some pain testing procedures (these are 
described in more detail below). You will then receive a capsule and an oral liquid. These contain 
different study medications for you to swallow. The medications you receive may contain a prescription 
stimulant, a prescription cannabinoid (related to the active ingredient in cannabis or marijuana), 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 
will know what combination of medications you have received. However, in the case of an emergency, a 
study doctor can quickly find out what medications you received.  
 
After you receive the study medications, we will ask you to continue completing questionnaires, 
computerized tasks, and pain testing procedures at regular intervals throughout the session day. We will 
also collect information about how your body is responding to the study medications, by collecting your 
blood pressure, heart rate, pupil diameter, and other measures of biological response. At the end of the 
session, we will provide you with a taxi ride home. The morning after a session, we will send you a 
secure web link that you can use to complete a final set of questions related to the session. This link will 
include only a small number of items that you answered with us during the session. We are collecting 
this information to make sure we have completely captured everything about how the study medications 
made you feel.  
 
You will be asked to complete 5 of these study sessions. Each session will be identical and we ask 
you to complete them about 1 week apart.  
 
Pain Testing Procedures:  
We will ask you to complete some pain testing procedures as part of this study. These tests help us to 
understand whether combining medications can reduce pain, and these data will help us learn whether 
there are new and better ways for the medical community to be treating pain in their patients.  
 
We will be using well-validated pain-testing procedures that are used by several other laboratories 
throughout the world. Some of the pain testing will include the application of a topical cream. 
 
It is important that you know that even though each procedure may produce some level of pain, we 
expect the pain to be relatively mild, and you will be able to end the procedure at any time (with no 
study-related consequences).  


 
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We are conducting several different pain procedures because they all activate different pain pathways, 
however the pain they produce is brief and none of these procedures are expected to produce any lasting 
pain or damage to you. Specifically, 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, which 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. We will also tap a place on your hand or elsewhere with some pencil-like 
objects. These may also be mildly painful, but again you will be able to stop the task whenever you 
want. Finally, we rub a cream on your hand that contains capsaicin, which is the chemical that makes 
some peppers hot. We will then use a machine that generates heat to evaluate your response to 
temperature-induced pain.  A staff member will introduce you to these procedures during the Screening 
visit so you will be able to make an informed decision about whether you’d like to participate in this 
study.  
 
4. 
What happens to data and biospecimens that are collected in the study?  
Johns Hopkins and our research partners work to advance science and public health.  The data and 
biospecimens we collect from you are important to this effort. 
 
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. 
 
If you join this study, you will not own the data and/or biospecimens collected from you as part of this 
research study. If researchers use them to create a new product or idea, including those that may have 
commercial value, you will not benefit financially from these efforts. 
 
What testing or procedures may be done with your biospecimens?  
Your biospecimens may be used for a variety of research purposes. The specific testing that will be part 
of this study includes testing for drugs of abuse, pregnancy, and general medical health. At the 
beginning of each study session, we will also collect a blood sample from women that we will use to 
analyze their hormone levels, because there is reason to believe that female hormones may change a 
woman’s response to the study medications.  
 
We would also like to collect an optional genetic sample from all study participants. This will be 
collected as a saliva sample and will be stored for future genetic testing. The goal of this sample will be 
to help us learn more about whether genetics impacts response to different FDA-approved medications. 
This sample is optional and your decision about whether to provide the sample will not impact your 
eligibility for the study. If you decide to provide us with a genetic sample, you should know that the 
Genetic Information Nondiscrimination Act (GINA) is a federal law that helps reduce the risk of 
discrimination by health insurers or employers based on your genetic information. GINA does not 
protect you from discrimination if you apply for other types of insurance (such as life, disability or long-
term care). GINA also does not protect you against discrimination based on an already-diagnosed 
genetic condition or disease. 
 
Genetic information is unique to you and your family. Even without your name or other identifiers, it 
may be possible to identify you or other members of your family with your genetic information.  
Johns Hopkins follows procedures so that people who work with your DNA information for research 
cannot discover it belongs to you, unless you have given consent. However, new techniques may be 
developed that in the future make it easier to link your genetic data to you, so we cannot promise that 
your genetic information will never be linked to you. 


 
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How will your data and/or biospecimens be shared now and in the future?  
Sharing data and/or biospecimens is part of research and may increase what we can learn from this study. 
 
Often, data/biospecimen sharing is required as a condition of funding or for publishing study results.  It 
also is needed to allow other researchers to validate study findings and to come up with new ideas. 
 
Your data and/or biospecimens may be shared:  
 directly with research collaborators, other researchers, sponsors, government agencies, 
publishers of papers and other research partners  
 through government or other databases/repositories  
 
Data/biospecimen sharing could change over time, and may continue after the study ends. 
 
We will do our best to protect and maintain your data/biospecimens in a safe way.  Generally, if we 
share your data/biospecimens without identifiers (such as your name, address, date of birth) further 
review and approval by an IRB is not needed.  However, when we share data/biospecimens, we limit the 
uses of the information and whether these data/biospecimens can be shared with another research team.  
If data/biospecimens are shared with identifiers, further IRB review and approval may be needed and the 
IRB will determine whether additional consent is required.  
 
Johns Hopkins researchers may also use the biospecimens collected in this study for future research 
purposes, which may include gene sequencing and genetic testing. Each cell contains your complete 
DNA.  Gene sequencing of your DNA provides researchers with the code to your genetic material. This 
future research may be unrelated to the current study and may include outside collaborators.  
Because science constantly advances, we do not yet know what future testing may include. If 
biospecimens are tested/used in ways not described above, further IRB review and approval may be 
needed and the IRB will determine whether additional consent is required. 
 
If you are not comfortable with the use of your data/biospecimens in future research, you may not want 
to participate in this study. However, you can decline the collection and storage of the genetic 
biospecimen for future research.  
 
Will you allow us to store and use the genetic biospecimens we collect for this study for future 
research? 
 
 
 
 
 
 
YES     ________________________ 
 
 
Signature of Participant 
 
 
 
 
 
 
NO      ________________________ 
Signature of Participant 
 
 
 
 


 
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5. 
What are the risks or discomforts of the study? 
 
Study Drugs:  
The largest risk of this study is associated with the medications you will receive. Side effects of the 
medications 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 medication-related side 
effects.  
 
It is important that you understand the potential side effects that you could experience from the study 
medications. These medications have been administered to people previously either as treatments for 
different medical illnesses or in other experimental studies. Below is a list of side effects that have been 
reported by some people who have taken these medications, however it is important to remember that 
some of these side effects may be related to the medical illnesses being treated and not a result of the 
medication itself.  Side effects are also more likely to happen when the medications are taken for several 
days in a row, which is different from how you will be taking the medications in this study. 
 
 Dermatologic: Rash (7-13%); Reddening of the face (2%), Itchy skin, 1-8%) 
 Gastrointestinal: Constipation (7-31%), Nausea (9-28%), Decrease in Appetite (16-22%), Diarrhea 
(9-20%), Vomiting (6-14%) 
 Cardiovascular: Low blood pressure (less than 2%), Fainting (less than 2%) 
 Immunologic: Reoccurrence of viral, fungal or other infections (41%).  The frequency of this side 
effect came from studies where subjects received the dose continuously for 14 weeks.  It is unlikely 
that you will experience this effect with the same frequency due to the lower doses and infrequent 
administration in this study. 
 Neurologic: Weakness  or Dizziness (1-11%), Headache (1-12%), Sleepiness(2-25%), Coma (less 
than 2%), Jerking of muscles (less than 2%), Increased intracranial pressure (less than 2%), 
Difficulty Sleeping, Insomnia, or Sleep Disorder (% not specified) 
 Psychiatric: Suicidal thoughts or behaviors (less than 2%) 
 Respiratory: Brief stop in breathing (less than 1%), Stopping breathing (less than 2%), Not breathing 
enough oxygen(% not reported) 
 Hepatic: Increased liver enzyme levels (8-16%) 
 Other: Drug dependence/Addiction or Drug Withdrawal (less than 1%), Fatigue or Feeling generally 
unwell (% not reported) 
 
It is important for you to know that, in extreme cases, these medications may cause your breathing to 
slow down or stop. They could also cause a severe allergic reaction or even death. You will undergo 
extensive medical testing during the Screening visits to determine 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. 
 
Risks from Combining the Study Medications:  
Although there is no evidence that combining the study medications results in negative side effects, it is 
always possible there may be some interactions between these medications that are not yet known.  We 
will carefully monitor emerging medical information about these drugs and will discontinue the study 
medications if new information indicates these medications should not be combined.  
 
 
 
 


 
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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. 
 
Capsaicin: 
Capsaicin is the main ingredient in hot peppers, and is used as an over-the-counter drug for the treatment 
of pain in products like Icy Hot. The dose of capsaicin we are using is higher than what is available over 
the counter, although it is less than half of the dose in a single habanera pepper. Capsaicin does cause 
some pain that is similar to how a hot pepper may feel when it is eaten. Capsaicin may produce some 
local redness and swelling that generally disappears within a day. The area of skin where the capsaicin is 
applied could be sensitive for up to 48 hours. Capsaicin may cause a burning feeling in the eyes or other 
areas of the body if accidentally rubbed onto other skin areas.  We will take precautions to make sure 
this does not happen. We will limit the exposure area to a small square on the back of the hand and will 
wash the capsaicin off with alcohol after each session. If needed, we can use some ice to reduce any 
continued discomfort you may experience. 
 
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. 
 
Legal Risks:  
It is possible that your urine samples will test positive for medications that could be considered abusable 
by your employers or law enforcement professionals (e.g., stimulants, cannabinoids, opioids). If this is a 
concern to you then, with your permission, we can provide you with a letter that confirms your 
participation in the study and the potential for you to test positive for drugs that could be considered 
abusable for up to 7 days following a study session.  
 
ECG:  
An ECG will be conducted to determine that you heart is healthy enough for study participation. To 
conduct the ECG you will have electrodes placed on your chest, and you may find these cold or 
uncomfortable, though they are not expected to produce any pain. It is possible that the ECG may reveal 
abnormalities in your heart functioning that could be clinically significant. In these cases, the study 
medical team will inform you of the abnormalities and will provide you with relevant information you 
need to follow-up with your own doctor. 
 
Interviews or 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. 
 
Confidentiality:  
There is the risk that information about you may become known to people outside this study. 
 
Unknown risk 
There may be side effects and discomforts that are not yet known.   
 
6. 
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 prior to every study session. Any 
woman who is found to be pregnant will not receive study medication and will be discharged from the 
study.  


 
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It is unknown whether this research may hurt an embryo or fetus.  
 
7. 
Are there benefits to being in the study? 
There is no direct benefit to you from being in this study. However, your participation in the study will 
help us to learn more about how to better treat pain, and whether certain combinations of medications 
should be used for that purpose.  
 
8. 
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. 
 
9. 
Will it cost you anything to be in this study?   
No.  
 
You will receive a separate Insurance and Research Participant Financial Responsibility Information 
Sheet (Sheet). This Sheet will give you the following information: 
 The procedures, tests, drugs or devices that are part of this research and that will be paid for by 
the study (no cost to you).   
 The procedures, tests, drugs or devices that will be billed to you and/or your health insurer.  If 
you have health insurance, you will be responsible for any co-pays or deductibles not covered by 
your insurance.  
 
10. 
Will you be paid if you join this study? 
You will be compensated up to $1300 for your time in the study, 
and your earnings are illustrated in this table. You will receive each 
session payment at the end of the session.  
 
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 
 
11. 
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 leave the study early, Johns Hopkins may use or share your health information that it has already 
collected if the information is needed for this study or any follow-up activities.  
 
12. 
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.  
Visit 
Payment 
Screening 
$50 (May be split 
into several 
payments) 
Session 1 
$150 
Session 2 
$200 
Session 3 
$250 
Session 4 
$300 
Session 5 
$350 
Total 
$1300 


 
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Combined Parental Permission/Informed Consent/Authorization December 2018 Version 16 
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. 
 
13. 
How will your privacy be maintained and how will the confidentiality of your data 
be protected?  
 
HIPAA Authorization for Disclosure of Protected Health Information  
 
What information is being collected, used, or shared? 
To do this research, we will need to collect, use, and share your private health information.  By signing 
this document, you agree that your health care providers (including both Johns Hopkins Medicine and 
others) may release your private health information to us, and that we may use any and all of your 
information that the study team believes it needs to conduct the study.  Your private information may 
include things learned from the procedures described in this consent form, as well as information from 
your medical record (which may include information such as HIV status, drug, alcohol or STD 
treatment, genetic test results, or mental health treatment). 
 
Who will see, use or share the information?  
The people who may request, receive, or use your private health information include the researchers and 
their staff who may be a part of Johns Hopkins Health System, Johns Hopkins University or the Johns 
Hopkins Applied Physics Laboratory.  Additionally, we may share your information with other people at 
Johns Hopkins, for example if needed for your clinical care or study oversight.  To improve coordination 
of your research and clinical care, some information about the study you join will be included in your 
electronic medical record.   
 
By signing this form, you give permission to the research team to share your information with others 
outside of Johns Hopkins.  This may include the sponsor of the study and its agents or contractors, 
outside providers, study safety monitors, government agencies, other sites in the study, data managers 
and other agents and contractors used by the study team.   
 
We try to make sure that everyone who sees your information keeps it confidential, but we cannot 
guarantee that your information will not be shared with others.  If your information is disclosed by your 
health care providers or the research team to others, federal and state confidentiality laws may no longer 
protect it.   
 
Do you have to sign this Authorization? 
You do not have to sign this Authorization, but if you do not, you may not join the study. 
 
How long will your information be used or shared?  
Your Authorization for the collection, use, and sharing of your information does not expire. 
Additionally, you agree that your information may be used for similar or related future research studies. 
 
What if you change your mind? 
You may change your mind and cancel this Authorization at any time.  If you cancel, you must contact 
the Principal Investigator in writing to let them know by using the contact information provided in this 
consent form.  Your cancellation will not affect information already collected in the study, or information 
that has already been shared with others before you cancelled your authorization. 
 
 


 
Approved November 1, 2021 
Date: November 1, 2021 
Principal Investigator: Kelly Dunn, Ph.D. 
Application No.: IRB00214289 
 
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How will your information be protected?  
This study will collect identifiable information (such as your name and date of birth). This information 
is necessary to ensure that we have enrolled you into the study properly. However the research team 
takes your confidentiality very seriously. We will collect only the minimal identifiable information 
necessary for this study. We will assign a unique study number to you that will be used on all of your 
study forms, and we will store any document that states your identifiable information in a separate 
physical location away from any study questionnaires so that your study number can not be immediately 
linked. Only staff members who are approved to work on this study and who have completed 
appropriate safety trainings will be permitted access to these forms. All of your information will be 
stored in study binders in locked rooms. Your data will be stored on computer files on encrypted and 
secure computers.  
 
14. 
What is a Certificate of Confidentiality? 
Your study information will also be protected by a Certificate of Confidentiality. This Certificate allows 
us, in some cases, to refuse to give out your information even if requested using legal means. 
 
It does not protect information that we have to report by law, such as child abuse or some infectious 
diseases. The Certificate does not prevent us from disclosing your information if we learn of possible 
harm to yourself or others, or if you need medical help. 
 
Disclosures that you consent to in this document are not protected. This includes putting research data in 
the medical record or sharing research data for this study or future research. Disclosures that you make 
yourself are also not protected. 
 
15. 
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.   
 
The costs for any treatment or hospital care you receive as the result of a study-related injury that are not 
covered by a health insurer will be billed to you. 
 
By signing this form, you will not give up any rights you have to seek compensation for injury.  
 
16. 
What other things should you know about this research study? 
During the study, we will tell you if we learn any new information that might affect whether you wish to 
continue to participate. 
 
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. 
 
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 doctor and other physicians who treat you.  When the 
study is completed, all the information in your medical record will be available to you. 
 


 
Approved November 1, 2021 
Date: November 1, 2021 
Principal Investigator: Kelly Dunn, Ph.D. 
Application No.: IRB00214289 
 
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What is the Institutional Review Board (IRB) and how does it protect you?  
This study has been reviewed by an Institutional Review Board (IRB), a group of people that reviews 
human research studies. The IRB can help you if you have questions about your rights as a research 
participant or if you have other questions, concerns or complaints about this research study.  You may 
contact the IRB at 410-502-2092 or jhmeirb@jhmi.edu.  
 
What should you do if you have questions about the study, or are injured or ill as a result of being 
in this study?  
Call the principal investigator, Dr. Kelly Dunn, Ph.D. 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.   
 
If you have an urgent medical problem or think you are injured or ill because of this study, call 911 or 
go to your local emergency department.  You should also call Dr. Traci Speed, M.D. during regular 
office hours, or after hours/weekends at 410-870-7139.   
 
17. 
Optional Study Components: 
This part of the consent form is about optional component(s) of the study that you can choose to take 
part in or not. You can still take part in the main study even if you say “no” to this/these optional 
component(s).  
 
Future Contact 
We would like your permission for our research team to contact you in the future.  Please note that your 
decision below does not prevent other researchers at Johns Hopkins from contacting you about other 
research. 
 
Please sign and date your choice below: 
 
 
 
 
 
 
YES    ________________________  
 
______________ 
Signature of Participant 
 
 
Date 
 
 
 
 
 
 
NO     ________________________ 
 
______________ 
Signature of Participant 
 
 
Date 
 
 
 
 
 


 
Approved November 1, 2021 
Date: November 1, 2021 
Principal Investigator: Kelly Dunn, Ph.D. 
Application No.: IRB00214289 
 
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18. 
What does your signature on this consent form mean?  
Your signature on this form means that you have reviewed the information in this form, you have had a 
chance to ask questions, 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 
 
 
 
I have received the separate Insurance and Research Participant Financial Responsibility Information Sheet.   
 
 
 
 
 
 
________________________________________________________________________________________________________________________ 
Signature of Participant, LAR or Parent/Guardian  
 
 
(Print Name) 
 
 
 
Date/Time 
 
 
NOTE: A COPY OF THE SIGNED, DATED CONSENT FORM MUST BE KEPT BY THE PRINCIPAL INVESTIGATOR AND A COPY 
MUST BE GIVEN TO THE PARTICIPANT.  IF APPROPRIATE FOR THIS STUDY, A SCANNED COPY OF THE SIGNED CONSENT 
FORM SHOULD BE UPLOADED TO THE PARTICIPANT’S EPIC/EMR RECORD (UNLESS NO MEDICAL RECORD EXISTS OR 
WILL BE CREATED).  
 
 


 
Approved November 1, 2021 
Date: November 1, 2021 
Principal Investigator: Kelly Dunn, Ph.D. 
Application No.: IRB00214289 
 
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DOCUMENTATION OF PHYSICIAN/MID-LEVEL PROVIDER CONSENT PROCESS 
 
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 AND A COPY 
MUST BE GIVEN TO THE PARTICIPANT.  IF APPROPRIATE FOR THIS STUDY, A SCANNED COPY OF THE SIGNED CONSENT 
FORM SHOULD BE UPLOADED TO THE PARTICIPANT’S EPIC/EMR RECORD (UNLESS NO MEDICAL RECORD EXISTS OR 
WILL BE CREATED).