Clinical trial NCT03929367
Conditions: Chronic Pain
Sponsor: Wake Forest University Health Sciences
Start date: 2019-05-10; Completion date: 2020-03-01
Enrollment: 11 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The primary goal of this protocol is to model change in oxytocin concentrations in plasma after intravenous (IV) administration. Additional measurements will be performed on sensory function that could be influenced by oxytocin during later time periods when blood samples are widely separated by time. This protocol will describe the pharmacokinetics (PK) of intravenous oxytocin in healthy adult men and adult,non-pregnant women. PK samples will be obtained after an injection of intravenous oxytocin 10 IU over 60 seconds.

Blood will be drawn for the PK samples prior to the oxytocin administration and then 11 times after administration.

There are two additional measures which will assess two different aspects of sensory function.

MEASURE 1: Light Touch Frequency Threshold In order to determine the highest frequency that specific nerve fibers can respond to, a simple device that produces an oscillatory / vibratory stimulus will be used on the hand. The subject places fingertips, palm, and palm side of the wrist sequentially and the device is set to slowly decrease the frequency of vibration from 1 kHz until the subject first perceives this. This is repeated three times at each site and takes less than 5 minutes in total. This will be performed before the oxytocin administration and 6 times after the administration of IV Oxytocin.

MEASURE 2: Sustained Heat The surface of the skin of the forearm or leg is heated to 113°F using a computer controlled thermode for a period of 5 minutes. This will be done before the IV Oxytocin and 4 times after the administration. A set of random thermal temperatures (98°F-122°F) will also be applied to the skin of the leg or forearm before the IV Oxytocin administration and 4 times after administration of IV Oxytocin.

Detailed description:
The primary goal of this protocol is to model change in oxytocin concentrations in plasma after intravenous administration, (oxytocin (Pitocin®), 10 IU) the investigators will also acquire tests of sensory function that could be modulated by oxytocin during later time periods when blood samples are widely separated by time. There are two measures which will assess two different aspects of sensory function.

MEASURE 1: Light Touch Frequency Threshold Light touch is subserved by a group of myelinated peripheral nerves with fast conduction in the Aβ range and which are capable of following high frequencies, being responsible for the sensation of vibration. This capability of individual nerve fibers to respond with high frequency also underlies our ability to sense a light touch moving across the body surface as in brushing.

In preclinical studies investigators have shown that, following injury, these light touch fibers lose their ability to follow high frequencies and, in some cases, no longer respond to mechanical stimulation at all. Oxytocin, when perfused around the neuronal cell bodies of these Aβ nerve fibers, partially restores their function, including their response to high frequency stimulation.

In order to determine the highest frequency that Aβ nerve fibers can respond to, the investigators have created a simple device that produces an oscillatory / vibratory stimulus which can be used on the hand. The subject places fingertips, palm, and volar aspect of the wrist sequentially and the device is set to slowly decrease the frequency of vibration from 1 kilohertz (kHz) until the participant first perceives this. This is repeated three times at each site and takes under 5 minutes in total.

The investigators anticipate that oxytocin will have no effect on normal Aβ fibers and that this measure will not change after oxytocin administration. This will provide important data to contrast with the expected efficacy of oxytocin in the setting of injury, to be studied in subsequent protocols.

MEASURE 2: Sustained Heat As part of a protocol used by the investigators in several studies, the surface of the skin of the forearm or leg is heated to 45°C using a computer-controlled thermode for a period of 5 minutes. This typically results in a slowly increasing pain experience, peaking at 5 minutes in the mild to low moderate range and has been tolerated by more than 150 subjects in studies over the past 14 years.

In an interim analysis of an ongoing clinical study in volunteers, the investigators noted that spinal injection of oxytocin, 15 μg (equivalent to 9 IU), that pain from this sustained heat was dramatically reduced over the 5 minutes of stimulus presentation. In contrast, spinal oxytocin had no effect on the stimulus-response relationship of pain to noxious heat over a 42-50°C range when the stimuli were presented for only 5 seconds. These data suggest that oxytocin reduces C-fiber mediated signaling of sustained heat pain, likely through a spinal site of action.

Drugs administered spinally have a much higher concentration in cerebrospinal fluid than plasma. Nonetheless, spinally administered drugs are typically absorbed to an extent and with a time course similar to that after intramuscular injection, and it is conceivable that the effect on sustained heat pain investigators are seeing in the spinal study reflect peripheral effects via systemic absorption. Thus, if the investigators see a similar reduction in response to sustained heat in this protocol of intravenous administration, the investigators will conclude that oxytocin is more likely activating peripherally than spinally.

Arms: arm 1: Oxytocin 10 IU administered once per intravenous injection
Interventions: intervention 1: Oxytocin
Intervention descriptions: intervention 1: Single IV administration of oxytocin

Protocol documents:
Prot_SAP_001.pdf: 
Version 6/11/2019  
 
 
 
Pharmacokinetics of intravenous oxytocin and effects on sensory 
function in healthy volunteers 
 
IRB00056413 
NCT03929367 
Version Date: 6/11/2019 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Version 6/11/2019  
BACKGROUND 
 
A large body of evidence in animals and in humans suggest that oxytocin can 
produce analgesia to experimental pain stimuli and relieve pain in acute and chronic 
clinical pain states.  For the past 8 years we have, under an NIH MERIT award, tested 
the role of the spinal cord in oxytocin’s actions by studies in rodents and clinical trials, 3 
of which are ongoing, of spinally injected oxytocin. 
 
The Pain Mechanisms Laboratory at Wake Forest is now in the process of 
assembling an NIH program project grant (P01) on the topic of oxytocin sites, 
mechanisms, and clinical applications for analgesia, and Dr. Eisenach will lead the 
clinical project in that proposal.  This IRB protocol is meant to obtain preliminary data 
critical to that NIH application in September, 2019. 
 
Determining the site(s) of action of oxytocin for analgesia in humans is critical to 
future clinical trials and drug development.  We will propose to use computer-controlled 
intravenous infusions of oxytocin to rapidly achieve and maintain targeted plasma 
concentrations.  By locking plasma concentrations and examining a wide concentration 
range, coupled with testing aimed to measure activity of oxytocin on peripheral nerves, 
in the spinal cord, and in the brain, we plan to identify infusion regimens that only target 
1 or 2 of these sites for clinical trials. 
 
WHY WE NEED TO DEFINE PHARMACOKINETICS OF OXYTOCIN 
 
In this IRB protocol we take the necessary first step towards computer-controlled 
intravenous infusions of oxytocin.  In this protocol we will describe the pharmacokinetics 
of intravenous oxytocin in healthy non-pregnant adult men and women.  We cannot 
program infusion devices for targeted concentrations without knowledge of oxytocin’s 
pharmacokinetics in this population of interest.  Although much is known of the 
pharmacodynamics of intravenous and intramuscular oxytocin to cause uterine 
contraction during pregnancy and in the postpartum period, we know virtually nothing 
about oxytocin’s pharmacokinetics in this setting and nothing in the nonpregnant 
population.  This reflects the fact that immunoassays used to measure oxytocin for the 
past 3 decades suffer critical limitations because the antibodies used are confounded by 
binding to oxytocin degradation products, particularly those that are tightly bound to 


Version 6/11/2019  
circulating proteins and presenting a large background of antigenicity to which these 
antibodies bound.  In a recent review of the state of our lack of knowledge regarding 
oxytocin disposition, it was noted that reports differ in resting and infused oxytocin 
concentrations in plasma by 2 to 3 orders of magnitude, and that the use of these 
assays essentially generate random numbers with no basis in reality [8]. 
 
Beginning in 2016 reports appeared of highly sensitive and specific assays of 
oxytocin in plasma and other biofluids using liquid chromatography coupled with mass 
spectroscopy (LC-MS) [2; 3; 6; 11].  A recent report included pharmacokinetics of 
oxytocin after intramuscular injection using LC-MS [3] with concentrations assayed by a 
commercial entity (Syneos Health, Princeton, NJ).  We have secured a quote from this 
company and will use them to measure oxytocin in de-identified samples from this 
protocol sent to their facility.  We note that pharmacokinetics from intramuscular 
administration cannot alone inform computer controlled infusion of intravenous oxytocin, 
necessitating data from this IRB protocol. 
 
RATIONALE FOR OTHER MEASURES BEYOND BLOOD SAMPLES IN THIS PROTOCOL 
 
Although the primary goal of this protocol is to model change in oxytocin 
concentrations in plasma after intravenous administration, we will also acquire tests of 
sensory function that could be modulated by oxytocin during later time periods when 
blood samples are widely separated by time.  There are two measures which will 
assess two different aspects of sensory function. 
MEASURE 1: LIGHT TOUCH FREQUENCY THRESHOLD 
 
Light touch is subserved by a group of myelinated peripheral nerves with fast 
conduction in the Aβ range and which are capable of following high frequencies, being 
responsible for the sensation of vibration.  This capability of individual nerve fibers to 
respond with high frequency also underlies our ability to sense a light touch moving 
across the body surface as in brushing. 
 
In preclinical studies we have shown that, following injury, these light touch fibers 
lose their ability to follow high frequencies and, in some cases, no longer respond to 
mechanical stimulation at all [1].  Oxytocin, when perfused around the neuronal cell 


Version 6/11/2019  
bodies of these Aβ nerve fibers, partially restores their function, including their response 
to high frequency stimulation. 
 
In order to determine the highest frequency that Aβ nerve fibers can respond to, 
we have created a simple device that produces an oscillatory / vibratory stimulus which 
can be used on the hand.  The subject places fingertips and volar aspect of the wrist 
sequentially and the device is set to slowly decrease the frequency of vibration from 1 
kHz until the subject first perceives this.  This is repeated three times at each site and 
takes under 5 minutes in total.  More details are provided in the Appendix. 
 
We anticipate that oxytocin will have no effect on normal Aβ fibers and that this 
measure will not change after oxytocin administration.  This will provide important data 
to contrast with the expected efficacy of oxytocin in the setting of injury, to be studied in 
subsequent protocols. 
MEASURE 2: SUSTAINED HEAT 
 
As part of a protocol used by us in several studies, the surface of the skin of the 
forearm or leg is heated to 45°C using an FDA approved, Peltier-controlled thermode for 
a period of 5 minutes (TSA®, Medoc, Ramat Yishai, Israel).  This typically results in a 
slowly increasing pain experience, peaking at 5 minutes in the mild to low moderate 
range and has been tolerated by more than 150 subjects in studies over the past 14 
years. 
 
In an interim analysis of an ongoing clinical study 
in volunteers, we noted that spinal injection of oxytocin, 
15 μg (equivalent to 9 IU), that pain from this sustained 
heat was dramatically reduced over the 5 minutes of 
stimulus presentation (adjacent figure). In contrast, 
spinal oxytocin had no effect on the stimulus-response 
relationship of pain to noxious heat over a 42-50°C 
range when the stimuli were presented for only 5 
seconds.  These data suggest that oxytocin reduces C-
fiber mediated signaling of sustained heat pain, likely 
through a spinal site of action.  
 
Drugs administered spinally have a much higher 


Version 6/11/2019  
concentration in cerebrospinal fluid than plasma.  Nonetheless, spinally administered 
drugs are typically absorbed to an extent and with a time course similar to that after 
intramuscular injection, and it is conceivable that the effect on sustained heat pain we 
are seeing in the spinal study reflect peripheral effects via systemic absorption.  Thus, if 
we see a similar reduction in response to sustained heat in this protocol of intravenous 
administration, we will conclude that oxytocin is more likely activing peripherally than 
spinally. 
 
 


Version 6/11/2019  
Protocol 
Pharmacokinetics of intravenous oxytocin and effects on sensory 
function in healthy volunteers 
 
PRIMARY GOAL:  Measure oxytocin in plasma after brief intravenous infusion and model 
its pharmacokinetics. 
 
METHODS:  Equal numbers of healthy adult men and women will be recruited (ten 
total).  At least 1 day prior to study subjects will be trained to rate pain in response to 
heat applied to the lateral calf using a Peltier controlled thermode and to indicate when 
they first perceive a vibratory stimulus on the fingertips and wrist.   
Subjects will return for study visit two in which an intravenous catheter will be 
inserted in the arm and, after baseline measures of response to heat and determination 
of vibration frequency threshold, subjects will receive oxytocin (Pitocin®), 10 IU over  10 
minutes.  Venous blood samples (5 ml) will be obtained before and at 2, 5, 10, 15, 30, 
45, 60, 90, 120, 180, and 240 minutes after the end of the oxytocin administration by 
removal of blood from the intravenous catheter. 
 We will abandon an individual participant's study and schedule another 
participant should we be unable to successfully place the intravenous catheter. 
 
STUDY DESIGN 
Inclusion Criteria: We request permission to study up to 12 subjects so that we will 
have 10 evaluable subjects with complete sampling at all time periods. 
1. Male or female > 18 and < 60 years of age, Body Mass Index (BMI) <40. 
2. Generally in good health as determined by the Principal Investigator based on 
prior medical history, American Society of Anesthesiologists physical status I or II 
3. Normal blood pressure (systolic 90-140 mmHg; diastolic 50-90 mmHg) resting 
heart rate 45-100 beats per minute) without medication 
4. Female subjects of child-bearing potential and those < 1 year post-menopausal, 
must be practicing highly effective methods of birth control such as hormonal methods 
(e.g., combined oral, implantable, injectable, or transdermal contraceptives), double 
barrier methods (e.g., condoms, sponge, diaphragm, or vaginal ring plus spermicidal 


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jellies or cream), or total abstinence from heterosexual intercourse for a minimum of 1 
full cycle before study drug administration. 
Exclusion Criteria: 
 
1. Hypersensitivity, allergy, or significant reaction to any ingredient of Pitocin® 
2. Any disease, diagnosis, or condition (medical or surgical) that, in the opinion of 
the Principal Investigator, would place the subject at increased risk (active gynecologic 
disease in which increased tone would be detrimental e.g., uterine fibroids with ongoing 
bleeding), compromise the subject’s compliance with study procedures, or compromise 
the quality of the data 
3. Women who are pregnant (positive result for serum pregnancy test at screening 
visit), women who are currently nursing or lactating, women that have been pregnant 
within 2 years 
4. Subjects with neuropathy, chronic pain, diabetes mellitus, or taking 
benzodiazepines or pain medications on a daily basis. 
 
Study Visit 1:  The participant will report to the Clinical Research Unit (CRU) or 
Piedmont Plaza II  at least 1 day prior to study visit 2. The participant will review and 
sign the Informed Consent. After informed consent is adequately obtained, a detailed 
medical history will be obtained from the participant, female participants will have a 
urine sampled tested   to determine pregnancy status.  The research nurse will train the 
participants to estimate pain quantitatively using a 2 cm2 Peltier controlled thermode 
(TSA®) applied to a forearm with 5 sec presentation of stimuli at 39, 41, 43, 45, 47, 49, 
and 50°C, using a 11 point numerical verbal scale (NRS) anchored at 0 for no pain and 
10 for the worst pain imaginable.  Typically, the participant is exposed to temperatures 
between 380 and 510 C using a random staircase method. After this training, we will ask 
them to report pain intensity on the 0-10 NRS scale every minute for 5 minutes upon 
exposure to a 4 cm2  Peltier controlled thermode at 45°C.  Finally, they will place first the 
fingertips of their hand and then the volar wrist, on a device and report when they first 
perceive a sensation as the surface vibration frequency declines from 1 kHz to 1 Hz. 
We have found this training session significantly reduces anxiety and variability in pain 
and hypersensitivity ratings on subsequent study days.  


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Study Visit 2  
On the second visit, the participant will report to the CRU, in the morning after 
having had nothing to eat or drink since midnight. A peripheral intravenous catheter will 
be inserted into a vein in an upper extremity and lactated Ringers solution infused at 1.5 
ml/kg/hr for the duration of the study. After obtaining baseline measures (random 
presentation of 5 sec heat stimuli between 39 and 50°C, 5 minute presentation of a 
45°C stimulus, and vibration frequency perception threshold as described in Visit 1), 
oxytocin (Pitocin®, 10 IU) will be administered intravenously over 10 minutes. 
Venous blood will be sampled (5 ml) before the infusion and at 2, 5, 10, 15, 30, 45, 
60, 90, 120, 180, and 240 minutes after oxytocin injection via the indwelling intravenous 
catheter.  We will also repeat vibration frequency perception threshold in fingertips  and 
wrist between the samples after samples at 5, 
20, 45, 60, 120, and 180 minutes.  In addition, 
we will ask them to rate pain intensity every 
minute for 5 minutes with a 45° stimulus after 
samples at 30, 60, 120, and 180 minutes (adjacent figure) and rate pain intensity to 
single, 5 second duration stimuli from 39°C to 50°C after samples at 60, 120, and 180 
minutes as on the first visit.  
Safety and Monitoring: 
 
Assessment of Side Effects:  Significant side effects are defined as changes > 30% 
from baseline in the mean arterial pressure, HR, or oxyhemoglobin pulse oximetry < 90. 
Any unexpected or serious side effects will be reported to the IRB within 24 hrs. 
Peripheral oxyhemoglobin saturation, BP and HR will be measured non-invasively 
before and 15, 30, 60, 120, 180, 240, minutes after intravenous oxytocin injection. If 
either BP or HR change by > 30%, or oxyhemoglobin saturation decreases to less than 
90, and require treatment, these vital signs will be repeated at 5-minute intervals until 
vital signs are stabilized.  
Treatment of Side Effects: Mean blood pressure elevations greater than 30% of 
baseline will be treated with labetalol 5-15 mg IV incrementally until BP elevation is less 
than 30% elevated. Reductions in mean BP > 30% of baseline will be treated with 
incremental ephedrine 5-20 mg, IV. Heart rate (HR) reductions or elevations > 30% of 


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baseline will be treated with incremental glycopyrolate 0.2 mg IV or propranolol 0.2 mg 
IV, respectively. Peripheral oxyhemoglobin desaturation (< 90) will be treated with 
supplemental oxygen, nasal cannula, face mask, or non-rebreathing mask depending 
upon the degree desaturation and the response to therapy.  
 
RISKS 
 
Risks of intravenous cannulation include pain on insertion and bruising at the 
site.  Risks from the FDA approved heat stimulus device are pain, and the subject can 
stop testing at any time if the pain they perceive is such that they do not want to 
continue.  Please note that these devices are used in many pain clinics routinely and 
have multiple fail-safe designs to avoid thermal burn.  Risks from the non-regulatory 
vibratory device are related only to microshock and are addressed in the Appendix. 
 
Risks of oxytocin are primarily restricted to uterine contraction in the presence of 
pregnancy, since oxytocin receptors are not present in the non-pregnant uterus 
(Package insert attached). 
Additionally there is the possibility of a feeling of being flushed, headache and 
increased heart rate with no significant change in blood pressure during or immediately 
after the infusion. These events have been reported by previous participants but were 
short lived, lasting approximately 12-15 minutes. 
 
 
HUMAN SUBJECTS 
All studies in volunteers will be performed in the CRU, which includes monitoring 
and resuscitation equipment and trained nursing support staff, or in in-patient settings of 
the Wake Forest Baptist Medical Center. All studies will be approved by the IRB and 
written informed consent obtained. The Project Investigators have all performed similar 
studies in volunteers and patients. The purpose of the study and all risks will be 
discussed with each volunteer, and all questions will be answered prior to obtaining 
written informed consent. Risks to be discussed include discomfort with needle and 
catheter insertion. All data acquired will remain confidential with no reference to 
individuals in publications.   


Version 6/11/2019  
Data Safety Monitoring Plan 
 
Although the use of oxytocin in this protocol is outside FDA approval for oxytocin 
administration during labor or in the postpartum period, the dose to be studied is similar 
to or less than that of multiple recent studies in healthy volunteers with intranasal 
oxytocin purchased over the counter in the US [4-7; 9-21] and without description of 
adverse events.  For these reasons, we do not propose a data safety monitoring 
committee or special safety evaluation beyond those required by IRB regulations. 
Minority, Gender, and Children Participation 
Both sexes and races and ethnicities will be actively recruited in this small study.  
Children under age 18 are not included in these protocols because this protocol 
because the safety of this product has not been established in children.  
 
Volunteer Payment 
Participants will be paid a total of $300 according to the following payment 
schedule which we have used throughout the last 2 cycles of this grant's protocols. We 
believe that this payment schedule is fair and appropriate, paying for each procedure 
attempted and an additional payment for completion of the entire study.  
Completion of study 1: $25 
Placement of IV: $25 
Completion of entire study: $250 
Volunteer must complete all of the above phases to receive this payment. 
 
Long-term Follow-up 
Volunteers will be contacted daily within the following week and questioned about 
adverse events from the study. 
 
STATISTICAL RATIONALE 
Primary outcome measure is the concentration of oxytocin in plasma at defined times 
after intravenous infusion.  We request a convenience sample of 10 subjects for the 
purpose of preliminary data to provide variance estimates that will inform federal grant 


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submission for use of the pharmacokinetic parameters from this sample or proposal of a 
larger sample size to adequately characterize such parameters.  
 
 
 
 
REFERENCES 
[1] Boada MD, Gutierrez S, Aschenbrenner CA, Houle TT, Hayashida KI, Ririe DG, Eisenach 
JC. Nerve injury induces a new profile of tactile and mechanical nociceptor input from 
undamaged peripheral afferents. J Neurophysiol 2015;113(100):109. 
[2] Brandtzaeg OK, Johnsen E, Roberg-Larsen H, Seip KF, MacLean EL, Gesquiere LR, Leknes 
S, Lundanes E, Wilson SR. Proteomics tools reveal startlingly high amounts of oxytocin 
in plasma and serum. Scientific reports 2016;6:31693. 
[3] Fernando D, Siederer S, Singh S, Schneider I, Gupta A, Powell M, Richards D, McIntosh 
MP, Lambert P, Fowles S. Safety, Tolerability and Pharmacokinetics of Single Doses of 
Oxytocin Administered via an Inhaled Route in Healthy Females: Randomized, Single-
blind, Phase 1 Study. EBioMedicine 2017;22:249-255. 
[4] Gossen A, Hahn A, Westphal L, Prinz S, Schultz RT, Grunder G, Spreckelmeyer KN. 
Oxytocin plasma concentrations after single intranasal oxytocin administration - a study 
in healthy men. Neuropeptides 2012;46(5):211-215. 
[5] Kessner S, Sprenger C, Wrobel N, Wiech K, Bingel U. Effect of oxytocin on placebo 
analgesia: a randomized study. JAMA 2013;310(16):1733-1735. 
[6] Lee MR, Scheidweiler KB, Diao XX, Akhlaghi F, Cummins A, Huestis MA, Leggio L, 
Averbeck BB. Oxytocin by intranasal and intravenous routes reaches the cerebrospinal 
fluid in rhesus macaques: determination using a novel oxytocin assay. Molecular 
psychiatry 2017. 
[7] Leknes S, Wessberg J, Ellingsen DM, Chelnokova O, Olausson H, Laeng B. Oxytocin 
enhances pupil dilation and sensitivity to 'hidden' emotional expressions. SocCogn 
AffectNeurosci 2013;8(7):741-749. 
[8] Leng G, Sabatier N. Measuring Oxytocin and Vasopressin: Bioassays, Immunoassays and 
Random Numbers. J Neuroendocrinol 2016;28(10). 
[9] Liu R, Yuan X, Chen K, Jiang Y, Zhou W. Perception of social interaction compresses 
subjective duration in an oxytocin-dependent manner. eLife 2018;7. 
[10] Mameli S, Pisanu GM, Sardo S, Marchi A, Pili A, Carboni M, Minerba L, Trincas G, Carta 
MG, Melis MR, Agabio R. Oxytocin nasal spray in fibromyalgic patients. Rheumatology 
international 2014;34(8):1047-1052. 
[11] Quintana DS, Westlye LT, Alnaes D, Kaufmann T, Mahmoud RA, Smerud KT, Djupesland 
PG, Andreassen OA. Low-dose intranasal oxytocin delivered with Breath Powered 
device modulates pupil diameter and amygdala activity: a randomized controlled 
pupillometry and fMRI study. Neuropsychopharmacology 2019;44(2):306-313. 
[12] Rash JA, Campbell TS. The effect of intranasal oxytocin administration on acute cold 
pressor pain: a placebo-controlled, double-blind, within-participants crossover 
investigation. Psychosom Med 2014;76(6):422-429. 


Version 6/11/2019  
[13] Rash JA, Toivonen K, Robert M, Nasr-Esfahani M, Jarrell JF, Campbell TS. Protocol for a 
placebo-controlled, within-participants crossover trial evaluating the efficacy of 
intranasal oxytocin to improve pain and function among women with chronic pelvic 
musculoskeletal pain. BMJ open 2017;7(4):e014909. 
[14] Striepens N, Kendrick KM, Hanking V, Landgraf R, Wullner U, Maier W, Hurlemann R. 
Elevated cerebrospinal fluid and blood concentrations of oxytocin following its intranasal 
administration in humans. SciRep 2013;3:3440. 
[15] Tanaka A, Furubayashi T, Arai M, Inoue D, Kimura S, Kiriyama A, Kusamori K, Katsumi 
H, Yutani R, Sakane T, Yamamoto A. Delivery of Oxytocin to the Brain for the 
Treatment of Autism Spectrum Disorder by Nasal Application. Molecular pharmaceutics 
2018;15(3):1105-1111. 
[16] Tracy LM, Labuschagne I, Georgiou-Karistianis N, Gibson SJ, Giummarra MJ. Sex-specific 
effects of intranasal oxytocin on thermal pain perception: A randomised, double-blind, 
placebo-controlled cross-over study. Psychoneuroendocrinology 2017;83:101-110. 
[17] Tzabazis A, Kori S, Mechanic J, Miller J, Pascual C, Manering N, Carson D, Klukinov M, 
Spierings E, Jacobs D, Cuellar J, Frey WH, 2nd, Hanson L, Angst M, Yeomans DC. 
Oxytocin and Migraine Headache. Headache 2017;57 Suppl 2:64-75. 
[18] Walum H, Waldman ID, Young LJ. Statistical and Methodological Considerations for the 
Interpretation of Intranasal Oxytocin Studies. Biol Psychiatry 2016;79(3):251-257. 
[19] Wang YL, Yuan Y, Yang J, Wang CH, Pan YJ, Lu L, Wu YQ, Wang DX, Lv LX, Li RR, 
Xue L, Wang XH, Bi JW, Liu XF, Qian YN, Deng ZK, Zhang ZJ, Zhai XH, Zhou XJ, 
Wang GL, Zhai JX, Liu WY. The interaction between the oxytocin and pain modulation 
in headache patients. Neuropeptides 2013;47(2):93-97. 
[20] Zhang H, Wu C, Chen Q, Chen X, Xu Z, Wu J, Cai D. Treatment of Obesity and Diabetes 
Using Oxytocin or Analogs in Patients and Mouse Models. PLOS ONE 
2013;8(5):e61477. 
[21] Zunhammer M, Geis S, Busch V, Greenlee MW, Eichhammer P. Effects of intranasal 
oxytocin on thermal pain in healthy men: a randomized functional magnetic resonance 
imaging study. Psychosom Med 2015;77(2):156-166. 
 

ICF_000.pdf: 
Page 1 of 9
Adult Consent Form
3/17/2020
Department/Section of Anesthesiology
WAKE FOREST School of Medicine
PHARMACOKINETICS OF INTRAVENOUS OXYTOCIN AND EFFECTS ON 
SENSORY FUNCTION IN HEALTHY SUBJECTS
Informed Consent Form to Participate in Research
James C. Eisenach, M.D., Principal Investigator
SUMMARY
You are invited to participate in a research study. The purpose of this research is to evaluate the 
change of oxytocin in the blood after administration of oxytocin by intravenous (IV) route and 
the effects it may have on sensory testing.  You are invited to be in this study because you are a 
healthy subject. Your participation in this research will involve 2 visits and last approximately 8 
hours. 
Participation in this study will involve receiving thermal and vibratory sensory testing, IV 
administration of oxytocin and blood sampling.  All research studies involve some risks.  A risk 
to this study that you should be aware of is discomfort from the thermal/sensory testing and IV 
placement.  
Your participation in this study is voluntary.  You do not have to participate in this study if you 
do not want to.  This is not a treatment study and there are no additional choices. You will not 
lose any services, benefits, or rights you would normally have if you choose not to participate. 
The remainder of this form contains a more complete description of this study. Please read this 
description carefully. You can ask any questions if you need help deciding whether to join the 
study. The person in charge of this study is James C. Eisenach, M.D. If you have questions, 
suggestions, or concerns regarding this study or you want to withdraw from the study his/her 
contact information is:  James C. Eisenach, M.D.
   
   
   
If you have any questions, suggestions or concerns about your rights as a volunteer in this 
research, contact the Institutional Review Board at 
or the Research Subject 
Advocate at Wake Forest at 
.
WFU School of Medicine 
Institutional Review Board 
IRB Number: IRB00056413
Meeting Date Approved 3/19/2020          
Version Valid Until: 4/28/2020


Page 2 of 9
Adult Consent Form
3/17/2020
INTRODUCTION
You are invited to be in a research study. Research studies are designed to gain scientific 
knowledge that may help other people in the future. You are being asked to take part in this 
study because you are a healthy adult. Your participation is voluntary. Please take your time in 
making your decision as to whether or not you wish to participate. Ask your study doctor or the 
study staff to explain any words or information contained in this informed consent document that 
you do not understand. You may also discuss the study with your friends and family.
WHY IS THIS STUDY BEING DONE?
The purpose of this research study is to evaluate the level of oxytocin in the blood after 
administration of oxytocin (naturally occurring hormone made in the brain that transmits 
messages) by intravenous (IV) route and the effects it may have on sensory testing.  
HOW MANY PEOPLE WILL TAKE PART IN THE STUDY?
We will enroll up to 12 people 10 people at this research site. In order to identify the 10 subjects 
needed, we may need to screen and enroll as many as 12 because some people will not qualify to 
be included in the study.
WHAT IS INVOLVED IN THE STUDY?
You will have 2 study visits. Study visit 1 may be conducted in the he Clinical Research Unit 
(CRU) at Wake Forest Baptist Medical Center or in the Pain Research Unit at Piedmont Plaza II. 
Study visit 2 will be conducted in the CRU.  Study visit 1 will last approximately 2 hours and 
study visit 2 will last approximately 6 hours.
If you take part in this study, you will have the following tests and procedures:
PROCEDURES
Vital Signs: we will monitor your blood pressure, heart rate and oxygen saturation (amount 
of oxygen in your blood).  
Laboratory Testing: female participants of child-bearing potential will have a urine 
pregnancy to determine that they are not pregnant. 
Thermal Heat Testing: we will train you to accurately describe pain from a small (about the 
size of a penny) and a large (about the size of a half dollar) probe. The tip of the heat probe that 
will be applied to the skin on your forearm is about the size of a penny.  The tip of the heat probe 
that will be applied to your calf is about the size of a half dollar. The thermal heat probe will be 
controlled by a computer that is programmed to deliver temperatures that range from skin 
temperature up to a temperature that is hot (122 ºF) and uncomfortable, but does not burn your 
skin.
Vibratory/Sensory Testing: Oscillatory motion can be termed as the repeated motion in 
which an object repeats the same movement over and over.
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Intravenous injection of Oxytocin: we will place an intravenous catheter and administer a 
dose of oxytocin 
Study Visit 1
You will report to the (CRU) or Pain Research Unit at least 1 day prior to study visit 2. You will 
review and sign the Informed Consent. After informed consent is adequately obtained, a detailed 
medical history will be obtained. During this visit we will measure your blood pressure, heart 
rate, and we will place a clip on your finger which will measure the oxygen in your blood. 
Female participants of child-bearing potential will provide a urine sample for a pregnancy test. 
We will perform thermal heat training by applying thermal temperatures that range from 100°F 
to 122 °F with a 5 second presentation of varying temperatures to your forearm. We will ask you 
to rate each stimuli using an 11 point numerical verbal scale (NRS) anchored at 0 for no pain and 
10 for the worst pain imaginable.  After this training, we will then place a slightly larger probe 
on your lateral calf and warm the area to a temperature of 113F for 5 minutes.  During this five 
minute warming period we will ask you to give a pain rating each minute for any pain you are 
experiencing. 
Finally, we will place the fingertips of your dominant hand and then the inside wrist, on a device 
that will vibrate. We will ask you to tell us when you first feel the vibration or sensation. 
Study Visit 2 
On the second visit, the participant will report to the CRU, in the morning after having had 
nothing to eat or drink since midnight. A peripheral intravenous (IV) catheter will be inserted 
into a vein in your arm and we will begin an IV fluid solution for the duration of the study. After 
obtaining baseline measures from the thermal heat and vibratory/sensory testing that was 
performed on study visit 1, oxytocin will be administered intravenously over 10 minutes. We 
will draw a blood sample from the IV before the injection and at the following interval after the 
injection; 2, 5, 10, 15, 30, 45, 60, 90, 120, 180, and 240 minutes. The blood samples will be 
drawn from the IV catheter.  We will repeat the vibration/sensory testing on the fingertips,  and 
wrist 6 more times and the thermal heat testing of the 5 second, 100° to 122°F temperatures 3 
additional times, and the 113F temperature for 5 minutes 4 additional times.
You will have approximately 1 teaspoon of blood withdrawn from a vein 12 times throughout 
study visit 2. The total amount of blood withdrawn during the study will be approximately 2 
ounces.
HOW LONG WILL I BE IN THE STUDY?
You will be in the study for 2 visits, approximately 8 hours total.
We will call you daily for 5 days after study visit 2.
You can stop participating at any time. If you decide to stop participating in the study we 
encourage you to talk to the investigators or study staff first to learn about any potential health or 
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safety consequences. 
WHAT ARE THE RISKS OF THE STUDY?
Being in this study involves some risk to you. You should discuss the risk of being in this study 
with the study staff. Risks and side effects related to the thermal/ sensory testing and oxytocin 
we are studying include:
Heat Probe 
You may experience brief pain during the thermal heat testing.
Vibratory Testing
You may experience a mild vibration in fingers/hand/wrist.
Needle Insertions
You may experience discomfort, bruising and/or bleeding where the needle is inserted. 
Occasionally some people become dizzy lightheaded or feel faint. Infection may occur on rare 
occasions.  
Oxytocin
Oxytocin is approved by the Food and Drug Administration (FDA) for use in the dose and route 
of administration we are using. We will monitor you for many theoretical problems such as 
changes in your blood pressure, how fast your heart is beating, and your urge to breathe. We will 
treat any side effects that you may experience if the changes are enough to concern us.
There is the possibility of a feeling of being flushed (warm feeling), headache and increased 
heart rate with no significant change in blood pressure during or immediately after the infusion. 
These events have been reported by previous participants but were short lived, lasting 
approximately 12-15 minutes.
In addition, there is a slight risk of a breach of confidentiality.  We will do our best to protect 
your confidential information.  There also may be other side effects that we cannot predict. You 
should tell the research staff about all the medications, vitamins and supplements you take and 
any medical conditions you have. This may help avoid side effects, interactions and other risks.
Taking part in this research study may involve providing information that you consider 
confidential or private.  Efforts, such as coding research records, keeping research records secure 
and allowing only authorized people to have access to research records, will be made to keep 
your information safe.
You may experience discomfort, bruising and/or bleeding where the needle is inserted. 
Occasionally some people become dizzy lightheaded or feel faint. Infection may occur on rare 
occasions.  Frequent donation of blood can result in low iron in your blood (iron deficient 
anemia).  
If you donate blood to the American Red Cross, you should talk with the study doctor about 
whether or not it is safe to do so while participating in this study. You should not donate blood 
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more than 2 times per week and no more than approximately one pint (about 500 ml) of blood in 
an eight week period.
Reproductive Risks and other Issues to Participating in Research
Due to unknown risks and potential harm to the unborn fetus, sexually active women of 
childbearing potential must use a reliable method of birth control while participating in this 
study. Reliable methods of birth control are: abstinence (not having sex), oral contraceptives, 
intrauterine device (IUD), DepoProvera, tubal ligation, or vasectomy of the partner (with 
confirmed negative sperm counts) in a monogamous relationship (same partner). An acceptable, 
although less reliable, method involves the careful use of condoms and spermicidal foam or gel 
and/or a cervical cap or sponge. We encourage you to discuss this issue further with your 
physicians if you have any questions.
Pregnant women are excluded from participation in this study. Because some methods of birth 
control are not 100% reliable, a pregnancy test is required at least 10 days from your last normal 
menstrual period, if you are a sexually active woman of childbearing potential.
 ARE THERE BENEFITS TO TAKING PART IN THE STUDY?
You are not expected to receive any direct benefit from taking part in this research study. We 
hope the information learned from this study will benefit other people in the future.
WHAT OTHER CHOICES ARE THERE?
This is not a treatment study. Your alternative is to not participate in this study.
WHAT ARE THE COSTS?
All study costs, including any study medications and procedures related directly to the study, will 
be paid for by the study. Costs for your regular medical care, which are not related to this study, 
will be your own responsibility.
WILL YOUR RESEARCH RECORDS BE CONFIDENTIAL?
The results of this research study may be presented at scientific or medical meetings or published 
in scientific journals.  Your identity and/or your personal health information will not be disclosed 
unless it is authorized by you, required by law, or necessary to protect the safety of yourself or 
others.  There is always some risk that even de-identified information might be re-identified. 
Participant information may be provided to Federal and other regulatory agencies as required.  
The Food and Drug Administration (FDA), for example, may inspect research records and learn 
your identity if this study falls within its jurisdiction.
WILL YOU BE PAID FOR PARTICIPATING?
You will be paid $300 if you complete all the scheduled study visits. If you withdraw for any 
reason from the study before completion you will be paid as follows:   
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Completion of study visit 1: $25
Placement of IV: $25
Completion of all study related procedures:  $250
To receive payment, you must provide your social security number, name and address so that we 
can comply with IRS (Internal Revenue Service) reporting requirements.  When payments are 
reported to the IRS we do not let them know what the payment is for, only that you have been 
paid.  If you do not wish to provide this information you can still take part in this study but you 
will not be paid.
The findings from this research may result in the future development of products that are of 
commercial value. There are no plans to provide you with financial compensation or for you to 
share in any profits if this should occur.
WHO IS SPONSORING THIS STUDY?
This study is being sponsored by the Department of Anesthesiology at Wake Forest School of 
Medicine. The sponsor is providing money or other support to Wake Forest University Health 
Sciences to help conduct this study. The researchers do not, however, hold a direct financial 
interest in the sponsor or the product being studied.
WHAT HAPPENS IF YOU EXPERIENCE AN INJURY OR ILLNESS AS A 
RESULT OF PARTICIPATING IN THIS STUDY?
Should you experience a physical injury or illness as a direct result of your participation in this 
study, Wake Forest University School of Medicine maintains limited research insurance 
coverage for the usual and customary medical fees for reasonable and necessary treatment of 
such injuries or illnesses. To the extent research insurance coverage is available under this policy 
the reasonable costs of these necessary medical services will be paid, up to a maximum of 
$25,000. Wake Forest University Baptist Medical Center holds the insurance policy for this 
coverage. It provides a maximum of $25,000 coverage for each claim and is limited to a total of 
$250,000 for all claims in any one year. The Wake Forest University School of Medicine, and 
the North Carolina Baptist Hospitals, Incorporated do not assume responsibility to pay for these 
medical services or to provide any other compensation for such injury or illness. Additional 
information may be obtained from the Medical Center’s Director of Risk and Insurance 
Management, at 
.
If you are injured, the insurer may require information such as your name, social security 
number, and date of birth in order to pay for your care.  This is because the insurer is required by 
law to report any payments made to cover the care of any persons who are members of a 
government insurance plan to the Department of Health and Human Services.
You do not give up any legal rights as a research participant by signing this consent form. For 
more information on medical treatment for research related injuries or to report a study related 
illness, adverse event, or injury you should call James Eisenach at
 or after hours 
you should call the study coordinator at 
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WHAT ABOUT MY HEALTH INFORMATION?
In this research study, any new information we collect from you about your health or behaviors 
is considered Protected Health Information. The information we will collect for this research 
study includes: medical history and medication history.
If this research study involves the diagnosis or treatment of a medical condition, then Protected 
Health Information collected from you during this study may be placed in your medical record, 
and may be used to help treat you, arrange payment for your care, or assist with Medical Center 
operations. 
We will make every effort to keep your Protected Health Information private. We will store 
records of your Protected Health Information in a cabinet in a locked office or on a password 
protected computer. 
Your personal health information and information that identifies you (“your health information”) 
may be given to others during and after the study. This is for reasons such as to carry out the 
study, to determine the results of the study, to make sure the study is being done correctly, to 
provide required reports and to get approval for new products.  
Some of the people, agencies and businesses that may receive and use your health information 
are the research sponsor; representatives of the sponsor assisting with the research; investigators 
at other sites who are assisting with the research; central laboratories, reading centers or analysis 
centers; the Institutional Review Board; representatives of Wake Forest University Health 
Sciences and North Carolina Baptist Hospital; representatives from government agencies such as 
the Food and Drug Administration (FDA) or the Office of Human Research Protections (OHRP), 
the Department of Health and Human Services (DHHS) and similar agencies in other countries.  
Some of these people, agencies and businesses may further disclose your health information. If 
disclosed by them, your health information may no longer be covered by federal or state privacy 
regulations.  Your health information may be disclosed if required by law. Your health 
information may be used to create information that does not directly identify you. This 
information may be used by other researchers. You will not be directly identified in any 
publication or presentation that may result from this study unless there are photographs or 
recorded media which are identifiable.
Any Protected Health Information collected from you in this study that is maintained in the 
research records will be kept for an indeterminate period of time. This authorization does not 
expire. You will not be able to obtain a copy of your Protected Health Information in the 
research records until all activities in the study are completely finished. 
You can tell Dr. James C. Eisenach that you want to take away your permission to use and share 
your Protected Health Information at any time by sending a letter to this address:
James C. Eisenach, M.D.
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Institutional Review Board 
IRB Number: IRB00056413
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Version Valid Until: 4/28/2020


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However, if you take away permission to use your Protected Health Information you will not be 
able to be in the study any longer. We will stop collecting any more information about you, but 
any information we have already collected can still be used for the purposes of the research 
study.
By signing this form you give us permission to use your Protected Health Information for this 
study.
If you choose to participate in this study, your medical record at Wake Forest University Baptist 
Medical Center will indicate that you are enrolled in a clinical trial.  Information about the 
research and any medications or devices you are being given as a participant may also be 
included in your medical record.  This part of the medical record will only be available to people 
who have authorized access to your medical record.  If you are not a patient at this Medical 
Center, a medical record will be created for you anyway to ensure that this important information 
is available to doctors in case of an emergency.
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law.  This website will not include information that can identify you.  At most, the 
website will include a summary of the results.  You can search this Web site at any time. 
A North Carolina Baptist Hospital (NCBH) medical record will be created for all study 
participants. Information about your participation in the study will be placed in the NCBH 
medical record, along with any routine medical test results that were obtained at NCBH as part 
of this study. 
WHAT ARE MY RIGHTS AS A RESEARCH STUDY PARTICIPANT?
Taking part in this study is voluntary. You may choose not to take part or you may leave the 
study at any time. Refusing to participate or leaving the study will not result in any penalty or 
loss of benefits to which you are entitled. 
You will be given any new information we become aware of that would affect your willingness 
to continue to participate in the study.
This study will be enrolling students from the Wake Forest University Medical Center campus.  
In addition to your rights as a research participant noted in the previous section, as a student, you 
are under no obligation to participate in this study. You may refuse to participate or withdraw 
from the study at any time and for any reason without affecting your grades, performance 
evaluations, or assignments. You will not be pressured into participating in this research study by 
any statements or implied statements that your grades, performance evaluations or assignments 
will be affected by your willingness to enroll in the study. Your medical records/information will 
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Institutional Review Board 
IRB Number: IRB00056413
Meeting Date Approved 3/19/2020          
Version Valid Until: 4/28/2020


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not be used by the faculty, administration or study staff to make decisions regarding the status of 
your medical benefits. If you have questions regarding your enrollment in the study and your 
status as a medical student, please contact the Office of Student Services for additional 
information.
WHOM DO I CALL IF I HAVE QUESTIONS OR PROBLEMS?
For questions about the study or in the event of a research-related injury, contact the study 
investigator, Dr. James Eisenach at 
 or after hours you should call the study 
coordinator by calling 
.
The Institutional Review Board (IRB) is a group of people who review the research to protect 
your rights. If you have a question about your rights as a research participant, or you would like 
to discuss problems or concerns, have questions or want to offer input, or you want to obtain 
additional information, you should contact the Chairman of the IRB at 
 or the 
Research Subject Advocate at 
.
You will be given a copy of this signed consent form. 
SIGNATURES
I agree to take part in this study. I authorize the use and disclosure of my health information as 
described in this consent and authorization form.  If I have not already received a copy of the 
Privacy Notice, I may request one or one will be made available to me.  I have had a chance to 
ask questions about being in this study and have those questions answered.   By signing this 
consent and authorization form, I am not releasing or agreeing to release the investigator, the 
sponsor, the institution or its agents from liability for negligence.
Subject Name (Printed):_____________________________
Subject Signature: _________________________________ Date: ________Time:_______ am pm 
Person Obtaining Consent (Printed):_____________________________
Person Obtaining Consent:___________________________ Date:_________ Time:________ am pm
WFU School of Medicine 
Institutional Review Board 
IRB Number: IRB00056413
Meeting Date Approved 3/19/2020          
Version Valid Until: 4/28/2020