Defining a Pharmacokinetic and Pharmacodynamic Model for Peripheral Analgesia After Intravenous Oxytocin
Phase: PHASE2
Conditions: Acute Pain, Chronic Pain, Healthy Volunteer
Sponsor: Wake Forest University Health Sciences

Official Title:  Defining a Pharmacokinetic and Pharmacodynamic Model for Peripheral Analgesia after 
Intravenous Oxytocin
NCT05929339
IRB Approval Date:  08/15/2024

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Create a PK/PD Model for Peripheral Oxytocin Effect 
Principal Investigator: James C. Eisenach, M.D., Co-investigator(s): Douglas Ririe, M.D., 
Scott Miller, M.D., Steven Shafer, M.D. 
Sponsor or funding source: NIH 
Rationale for current application 
Both preclinical and clinical evidence suggests that oxytocin may serve as a novel pain 
therapeutic and potential disease-modifying agent to prevent the transition from acute to chronic 
pain. This follows from observations that pain resolves quicker in women after cesarean delivery 
than other surgeries [1], and that hypersensitivity resolves quicker in rodents when neuropathic 
injury is performed after delivery, an effect blocked by inhibition of oxytocin action [2, 3]. 
Oxytocin may act peripherally to affect pain after injury.  Since chronic pain is usually reduced 
acutely by peripheral nerve block, peripheral input is necessary, but most research assumes 
that input is normal and pain reflects ongoing central sensitization. We and others challenge 
these ideas, showing that touch sensitive nerve fibers are desensitized after injury whereas fast 
conducting pain nerve fibers are sensitized [4].  In rodents, oxytocin acutely moves these two 
abnormal signals after injury towards normal [5], suggesting a disease-modifying potential of 
oxytocin as a ‘vaccine’ against chronic pain after injury.  
Oxytocin itself is the only clinically available tool for translational studies in many areas – 
neuroprotection, anxiety, sleep, social behaviors, addiction, and pain.  Most rodent and human 
studies of oxytocin are small, lack strong scientific rigor, and only half of the clinical studies 
examining pain demonstrate efficacy.  Thus, we have minimal ability to understand oxytocin 
effects across species.  A critical problem is the complete lack of fundamental pharmacologic 
characterization for oxytocin, which is used clinically in obstetrics by titration-to-effect.  There 
are few PK and no PK/PD modeling studies of oxytocin in the literature, and the PK studies use 
RIA and ELISA assays which are unreliable [6].  
Under IRB00056413 we measured plasma oxytocin concentrations after IV 
administration, using an LC/MS assay [7].  Figure 1A shows individual (thin lines) and group 
(thick lines) after oxytocin, 10 IU (17 μg).  The first 3 individuals received a 1 min infusion, which 
was accompanied with headache and sensation of flushing (red lines) and the remaining 8 
volunteers received a 10 min infusion with 5 of 8 subjects experiencing symptoms.  These data 
were well fit to a 2-compartment PK model using NONMEM.  Note the large discrepancy 
between these data and a recent report [8] in which the same dose of oxytocin was infused over 
10 min and plasma oxytocin measured by radioimmunoassay (RIA). 
To assess peripheral effects, we used pain report to 5 minute exposure to a heat 
stimulus, since our studies in rodents shows that prolonged noxious heat sensitizes and 
increases activity the fast conducting pain fibers which are sensitive to oxytocin [9]. Figure 1B 
shows the modeled plasma oxytocin concentrations in the 11 subjects in Figure 1A and pain 

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report to a 5 min noxious heat exposure.  
The data were nicely fit to a PK/PD 
model yielding parameters of 25 min to 
peak effect, an EC50 of 10 pg/ml, and 
steepness of concentration response (γ) 
of 1 (green dashed lines). The goal of 
this PK study was to determine oxytocin 
PK and to explore a potential effect on 
pain from skin heating.  Under 
IRB00066136 we examined the time 
course of analgesia to skin heating by 
slower infusion of IV oxytocin (0.47 
µg/min for 30 min for a total dose 14 µg) 
in 10 volunteers. There were no adverse 
events with this dosing regimen, and the 
PK/PD model from the first study 
accurately predicted the time course of 
onset of analgesia during infusion and 
maintenance of analgesia after the 
infusion was stopped (Figure 1C). 
 
 
Based on this model, we predicted that 10 min infusions of oxytocin, 0.3, 1.3, and 7 µg 
would produce approximately 20, 50, and 80% maximum effect to reduce pain from 5 min 
application of heat.  We completed that study (IRB00079629) in February, 2023 and observed 
minimal impact on pain by of these infusion doses.  A more thorough modeling evaluation of the 
original preliminary data revealed a consistent oxytocin effect across both previous intravenous 
infusion studies and suggested that the original modeling led us to use doses below the 
threshold to achieve analgesia.  The revised modeling forms the basis for the oxytocin dosing to 
administered in the current application. 
 
Protocol 
 
Objective. The primary objective of the current IRB application is to define the time 
course of change in pain score after 5 min heating of the skin applied at intervals during and 
following infusion of intravenous oxytocin in order to create a PK/PD model for oxytocin-induced 
analgesia.  The proposed study design will advance the preliminary data by use of a dosing 
regimen predicted to produce the maximum achievable effect with oxyticn in a manner that will 
validate and more precisely describe PK/PD model from prelimary data. 
 
A secondary objective is to test for effects of subject sex or age on oxytocin effect. 
 
 
Overview. Equal numbers of adult men and women, age 18-75 will be recruited. 
Subjects will report to the Pain Clinical Research Unit (CRU) or the CTSI CRU for four visits, the 
first to confirm consent and train the individuals in all heat pain procedures, the second to infuse 
oxytocin intravenously, record heat pain ratings at 15 min intervals for 2 hr, then once more at 3 
hr, and the third and fourth to record heat pain ratings approximately 24 hr and 5-7 days after 
oxytocin infusion.  A PK/PD model will be generated from these PD measures (heat pain 
ratings). We will not withdraw blood and measure oxytocin for PK in these subjects nor in 
subsequent studies to be submitted to the IRB.  Rather, we will use the population PK model of 
intravenous oxytocin established from a past study of 11 volunteers and an ongoing study in 24 
other volunteers.  
 
Figure 1.  A) plasma oxytocin concentrations with 
LC/MS (red/black lines) compared to plasma by RIA 
(blue lines.  B) modeled plasma oxytocin concentrations 
(blue line) and observed (circles) and modeled (green 
dash) pain scores after 10 min infusion of 17 µg oxytocin. 
C) as in B) but after 30 min infusion of 14 µg oxytocin 
10) 

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Phase II trials 
 
Setting 
The training visit will occur at either the Pain CRU at Piedmont Plaza 2 or the CTSI 
CRU.  Drug study visits will occur on the main campus at CTSI CRU.  
 
 
Subjects selection criteria 
The study will enroll healthy subjects. 
 
Inclusion Criteria 
1. Male or female > 18 and < 75 years of age, Body Mass Index (BMI) <40. 
2. Generally in good health as determined by the Principal Investigator based on 
prior medical history, and as assessed to be American Society of Anesthesiologists 
physical status 1, 2 
3. For healthy volunteers, normal blood pressure (systolic 90-140 mmHg; diastolic 
50-90 mmHg) resting heart rate 45-100 beats per minute) without medication.  For 
those with hypertension, blood pressure controlled with anti-hypertensive medication 
and with a resting heart rate 45-100 beats per minute. 
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 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 urine 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 (located in any body location that is being 
treated), diabetes mellitus, or taking benzodiazepines or pain medications on a daily 
basis. 
5. Subjects with current or history of ventricular tachycardia, atrial fibrillation or 
prolonged QT interval. 
6. Subjects with past or current history of hyponatremia or at risk for hyponatremia; 
anyone taking thiazide diuretics, loop diuretics, combination diuretics, lithium, 
carbamazepine, enalapril, Ramipril, celecoxib, temazepam, gliclazide, glimepiride, 
glibenclamide, glipizide, omeprazole, pantoprazole, desmopressin, SSRI’s, MAOI, or 
the recreational drug ecstasy. 
7. Subjects with a known latex allergy. 
 
 
 
 

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Sample Size 
  
 
The projected sample size is 24 evaluable subjects with complete data sets.  We request 
to enroll up to 26 subjects. Our current estimates indicate that the confidence interval for studies 
of 21 individuals with pain intensity ratings in two preliminary studies will determine the 
pharmacodynamic parameters with a corrected confidence range < 20%. A corrected 
confidence range < 20% implies that mixed effect analysis will distinguish covariate effects in 
the range of 40% in a study with 21 or more subjects. This is the range at which the covariate 
effect may be clinically consequential. In practice, mixed-effects analysis with NONMEM is often 
sensitive to covariate effects smaller than predicted by preliminary analyses. The sample size is 
increased to 24 to provide covariate assessment for age, weight, and sex.  
 
Interventions and Interactions 
 
 
At all study visits participants will be queried regarding recent history of symptoms 
commonly associated with COVID-19 or recent close contacts with anyone with a positive 
COVID-19 test. 
 
Study Visit 1:   
 
The participant will report to the Pain CRU or the Wake Forest CTSI CRU. 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 pregnancy test performed to determine pregnancy status.  Vital signs to include 
blood pressure (BP), heart rate (HR), respiratory rate (Resp) and oxyhemoglobin saturation by 
pulse oximetry (POX) will be measured and recorded along with height and weight.  
Once eligibility has been determined the participant will be trained in study procedures. 
This will include pain ratings to brief (5 sec) heat stimuli on the lateral calf to 39, 41, 43, 45, 47, 
and 49⁰C and then a pain intensity rating each minute for 5 mins during heating to 45⁰C.  If the 
pain report to 45⁰C is ≤ 2 at the end of the 5 min, a second trial using 46⁰C will be done. If the 
46⁰C results in pain intensity ≤ 2, a third trial with 47⁰C will be performed, and if that trial results 
in pain intensity ≤ 2, a third trial with 48⁰C will be performed.  Subjects who have pain intensity ≤ 
2 with the 48⁰C 5-min stimulus will not be further studied. The duration for visit 2 will be 
approximately 2 hours. 
 
Study Visit 2  
On the second visit, the participant will report to the CTSI CRU. Baseline vital signs (BP, 
HR, Resp, POX) will be obtained for a baseline measurement, a catheter inserted into a 
peripheral vein in the upper extremity and pain report to 5 min heating of skin on the calf at the 
temperature determined in Visit 1 will be recorded.  Subjects will then receive two 30 min 
infusion of oxytocin, 17 µg (provided by the research pharmacy), with infusions separated by 30 
min. Pain ratings to 5 min heat pain testing will be performed at 15 min intervals for 2 hr, then at 
3 hr after initiation of the first infusion.  The first 5 min heat stimulus will end at 15 min after 
beginning the first oxytocin infusion in the first 8 subjects.  In the event that there is no effect of 
oxytocin on heat pain, we will stop recruitment and assess whether protocol amendment or 
termination will be requested.  If there is an effect, the remaining 16 subjects will be randomized 
to have the first 5 min heat stimulus end at 10 or 20 min after the first oxytocin infusion begins.  
In this fashion there will be 3 cohorts of 8 subjects each, thereby providing pain rating 
measurements in 8 subjects every 5 min after the first 5 minutes of the infusion. The duration for 
study visit 2 will be approximately 4 hours. 
 
 

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Study Visit 3  
On the third visit, the participant will report to the CRU approximately 24 hr after the 
beginning of the infusion (acceptable range 20-28 hr) and heat pain ratings acquired on 3 trials 
separated by 10 min. The duration for study visit 3 will be approximately 1 hour. 
 
Study Visit 4  
 
On the fourth visit, the participant will report to the CRU 5-7 days after the day of 
oxytocin infusion and heat pain ratings acquired on 3 trials separated by 10 min. The duration 
for study visit 4 will be approximately 1 hour. 
 
Safety and Monitoring: 
 
Assessment of Side Effects:  Peripheral oxyhemoglobin saturation, BP and HR will be 
measured non-invasively before and 5,10, 30, 60, 90 and 120 minutes after oxytocin infusion. 
Subjects will informed to report any subjective sensations during or after oxytocin administration 
and will be queried at the same intervals as vital sign monitoring for any subjective sensations.   
 
Treatment of Side Effects: Significant cardiorespiratory side effects include: 
a. Decreased BP with symptoms of hypotension (e.g., dizziness or 
lightheadedness) 
b. Blood pressure or HR changes >20% 
c. Pulse oximetry less than 94% that does not correct with several deep breaths. 
 
Treatment of BP elevations > 20% of baseline will be treated with labetalol 5-15 mg IV 
incrementally until BP elevation <20% elevated. Treatment of symptomatic hypotension or BP 
reductions >20% will be treated with incremental ephedrine 5-20 mg, IV. Heart rate (HR) 
reductions or elevations > 20% of baseline will be treated with incremental glycopyrrolate 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.  
 
Regardless of whether any treatment is required, subjects with significant side effects 
will be monitored more frequently (every 5 min for BP and HR; continuously for POX) until 
symptoms or signs resolve. 
 
Serious adverse events:  In addition to treatment, as described above, and timely reporting as 
required to the DSMC, IRB, and FDA, emergency treatment will be available within the CRU 
itself.  As such, an ACLS-certified health care professional will be on site or within 5 minutes of 
the CRU during each treatment session, and a crash cart containing medicine and equipment 
for emergency resuscitation, and an automated external defibrillator will be located on-site. 
 
Study Stopping Criteria:  Should significant cardiorespiratory or other side effects occur during 
oxytocin administration, the IV infusion will be stopped and the subject treated as indicated in 
Treatment of Side Effects.   
 
The study will be stopped if more than 2 individuals exhibit significant cardiorespiratory side 
effects or after any serious adverse event and future conduct of the study will be determined by 
recommendations from the DSMC, IRB, and FDA. 
 
 
 
 

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Outcome Measure(s) 
 
 
Primary Outcome Measure 
 
Name: Average verbal pain score (0-10) at one min intervals during the 5 min of skin 
heating 
 
Type: Primary 
 
Time Frame: For 180 minutes after the beginning of oxytocin infusion  
 
Description: Pain scores are measured each minute during 5 min heating of the skin of 
the calf, with temperature of the probe determined in visit one to obtain a pain score at the end 
of this period of > 2. 
 
  
Analytical Plan 
 
The primary analysis will use NONMEM to create a PK/PD model of oxytocin on average 
pain ratings each min for 5 min during the noxious heat stimulus.  To do so, pain scores over 
time will first be modeled using NONMEM with derived parameters of maximum effect (Emax), 
predicted concentrations from the PK/PD model to produce a 50% and 90% maximum drug 
effect (C50 and C90, respectively), the steepness of the dose response curve (γ), and the time 
to peak effect.  Inter-subject variability (e.g., biological variability) will evaluate additive, 
proportional, and exponential models. Residual intrasubject variability (e.g., noise) will typically 
require an additive and multiplicative error model. The influence of covariates (e.g., age, sex, 
weight) on model parameters will be analyzed by serial inclusion / exclusion, with significance 
determined by the likelihood ratio test (p < 0.01 if the decrease in -2 log likelihood exceeds 6.6 
(𝜒𝜒0.99
2
, df = 1)). Parameters will be estimated using first-order conditional estimate with η-ε 
interaction.  
 
 
Covariate effects deemed significant by likelihood ratio test will be validated using 
jackknife cross-validation [10]. Jackknife cross-validation provides an estimate of the utility of 
the covariate to inform the pharmacodynamics in a future individual, rather than merely 
characterize the pharmacodynamics in the individuals from which the model was derived. The 
jackknife cross-validation divides the data into N subsets. Each subset leaves out a single 
individual. The parameters of the model are re-estimated for each subset with and without the 
covariate being validated. The inaccuracy (mean ((|measured – predicted|) / predicted)), of the 
model with and without the covariate is measured in the excluded individual. The covariate is 
only being included in the final model if it the improvement in model accuracy in the N iterations 
is significantly greater than 0. Jackknife cross-validation helps compensate for NONMEM’s 
ability to identify very small covariate effects that do not meaningfully contribute to accuracy in 
future patients. 
 
 
Expected outcomes.  Based on pain ratings and an estimate of the PK/PD model from 
preliminary data (Fig 1), we anticipate that the maximum oxytocin effect is a 50-60% reduction 
in pain rating from the 5 min heat stimulus.   
 
Human Subjects Protection 
 
Subject Recruitment Methods 
 
Healthy subjects will be recruited from our current database of volunteers BG05-468, 
word of mouth and Be Involved website; The research nurses; Regina Curry, RN and Vonda 
McGee, LPN will conduct the recruitment of study subjects.  
 
Potential subjects from the database will be contacted via phone or email, per their 
request. Potential subjects from the Be Involved website will be contacted according to the 
information they provide.   

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Informed Consent 
Signed informed consent will be obtained from each subject.  Regina Curry, RN or Vonda 
McGee, LPN will obtain consent. Potential subjects will be consented in the CRU. A private 
room will be utilized during the consent process and all study visits. 
 
Confidentiality and Privacy 
Confidentiality will be protected by collecting only information needed to assess study 
outcomes, minimizing to the fullest extent possible the collection of any information that 
could directly identify subjects, and maintaining all study information in a secure manner.  To 
help ensure subject privacy and confidentiality, only a unique study identifier will appear on 
the data collection form.  Any collected patient identifying information corresponding to the 
unique study identifier will be maintained on a linkage file, store separately from the data.  
The linkage file will be kept secure, with access limited to designated study personnel.  
Following data collection subject identifying information will be destroyed 3 years after 
closure of the study, in confidential shredding disposal bins consistent with data validation 
and study design, producing an anonymous analytical data set.  Data access will be limited 
to study staff.  Data and records will be kept locked and secured, with any computer data 
password protected.  No reference to any individual participant will appear in reports, 
presentations, or publications that may arise from the study. 
 
Data and Safety Monitoring 
The principal investigator will be responsible for the overall monitoring of the data and safety 
of study participants.  The principal investigator will be assisted by other members of the 
study staff. 
 
The DSMP outlined below will provide appropriate oversight and monitoring to ensure the 
safety of participants, the validity of the data, and make intermittent recommendations whether 
to continue, modify or stop the study. The DSMP will utilize an independent DSMB to ensure the 
effective institution of the DSMP. 
 
This DSMB will have discretion to unblind any results, or conduct any inquiry needed to ensure 
the safety and efficacy of the trial at the request of the DSMB chair. The committee will maintain 
a written record of its meetings. 
 
Scope of Data Monitoring 
The primary source of the data will be adverse event reporting. 
 
 
Study admission data 
Monitoring of admission data will include the number of subjects requesting participation in the 
study, number of subjects screened and number of subjects admitted to the study. The DSMB 
may request a report of the reason why subjects were disqualified from participating in the 
study. For subjects admitted to the study, the DSMB will review eligibility criteria for admitted 
subject, any protocol deviations and/or violations, and the demographic distribution of the 
subjects by group. 
 
Protocol Compliance 
The DSMB will monitor the data to assess compliance with the protocols including the 
adherence to the randomization schedule. The DSMB will also monitor the quality and 
completeness of the data being collected, including the frequency of missing or erroneous data, 
and presence and frequency of outliers. 

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Safety Data 
Monitoring of safety data will include review of Adverse Events (AEs) and Serious Adverse 
Events (SAEs), trial retention, and reason for drop out. Safety information will be reported to the 
DSMB in an unblinded manner. Formal statistical analyses of the safety data may be requested 
by the DSMB. For SAEs, data will include all the adverse event data meeting the FDA definition 
of serious adverse events. In the assessment of SAEs, the DSMB will review each individual 
case including treatment group assignment. After each meeting of the DSMB, the secretary will 
forward a summary report of all serious and unexpected adverse experiences to the principal 
investigator to summarize the DSMB's review of the serious and unexpected adverse events 
reported. Furthermore, the DSMB will make a recommendation to continue, modify or halt the 
study protocol. This report will be transmitted to the Wake Forest University IRB and NIH. Safety 
data will be prepared for review following the enrollment of each 24 subjects. 
 
Establishing a DSMB Board membership 
The DSMB will be appointed by Dr. Eisenach and Dr. Ririe with the purpose of reviewing, 
approval, and monitoring the implementation of the DSMP. The DSMB will have two members 
encompassing multidisciplinary expertise who are not involved in the study protocol. Board 
members will have no financial and/or scientific ties to the outcome of the clinical trials to avoid 
any real or perceived conflict of interest. At the start of each new member's term, the individual 
will sign a confidentiality statement promising not to disclose any proprietary and nonproprietary 
data. The DSMB will include the following physicians; Laura Dean, M.D., Associate Professor of 
Anesthesiology and Director of Obstetric and Gynecologic Anesthesiology and Ashish Khanna, 
M.D., Associate Professor and Vice Chair for Research in Anesthesiology, Wake Forest School 
of Medicine. 
 
 
Board meeting schedule 
The board will have scheduled meetings twice a year and expedited meetings to review 
unexpected SAEs or other urgent issues that may arise during the trial. Unscheduled meetings 
may be initiated by the DSMB chair, Dr. Eisenach, or Dr. Ririe. The data to be reviewed by the 
DSMB will be available to the Board members. 
 
DSMB Recommendations: 
DSMB recommendations will be made in writing by The DSMB chair to Dr. Eisenach. The 
secretary will prepare meeting minutes for inclusion in the DSMB report. The draft report will be 
reviewed by all Board members prior to issuance of the final report. DSMB recommendations 
will then be forwarded to the NINDS program officer and Wake Forest University IRB. 
 
Volunteer Payment 
Participants will be paid a total of $500 according to the following payment schedule 
which we have used throughout the last 10 years. 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 visit 1: $50 
Study visit 2:  placement of IV-$25, IV infusions and thermal testing-$125 
Study visit 3:  thermal testing-$100 
Study visit 4:  thermal testing-$100 
Completion of all study related procedures: $100 
 

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If an IV cannot be placed on Study visit 2: subject will be compensated $50 and subject 
replaced. 
 
Long-term Follow-up 
Volunteers will be contacted daily within the following week and questioned about 
adverse events from the study. 
 
 
Reporting of Unanticipated Problems, Adverse Events or Deviations 
Any unanticipated problems, serious and unexpected adverse events, deviations or protocol 
changes will be promptly reported by the principal investigator or designated member of the 
research team to the IRB, DSMC and the FDA if appropriate. 
 
 
References 
1. 
Eisenach, J.C., et al., Resolution of pain after childbirth. Anesthesiology, 2013. 118(1): p. 
143-51. 
2. 
Aschenbrenner, C.A., et al., Modeling individual recovery after peripheral nerve injury in 
rats and the effects of parturition. Anesthesiology, 2014. 121(5): p. 1056-67. 
3. 
Gutierrez, S., et al., Reversal of peripheral nerve injury-induced hypersensitivity in the 
postpartum period: role of spinal oxytocin. Anesthesiology, 2013. 118(1): p. 152-9. 
4. 
Boada, M.D., et al., Nerve injury induces a new profile of tactile and mechanical 
nociceptor input from undamaged peripheral afferents. J Neurophysiol, 2015. 113(1): p. 
100-9. 
5. 
Boada, M.D., S. Gutierrez, and J.C. Eisenach, Peripheral oxytocin restores light touch 
and nociceptor sensory afferents towards normal after nerve injury. Pain, 2019. 160(5): 
p. 1146-1155. 
6. 
MacLean, E.L., et al., Challenges for measuring oxytocin: The blind men and the 
elephant? Psychoneuroendocrinology, 2019. 107: p. 225-231. 
7. 
Fernando, D., et al., 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: p. 249-255. 
8. 
Martins, D.A., et al., Effects of route of administration on oxytocin-induced changes in 
regional cerebral blood flow in humans. Nat Commun, 2020. 11(1): p. 1160. 
9. 
Boada, M.D., D.G. Ririe, and J.C. Eisenach, Post-discharge hyperpolarization is an 
endogenous modulatory factor limiting input from fast-conducting nociceptors 
(AHTMRs). Mol Pain, 2017. 13: p. 1744806917726255. 
10. 
Fiset, P., et al., Pharmacokinetics of computer-controlled alfentanil administration in 
children undergoing cardiac surgery. Anesthesiology, 1995. 83(5): p. 944-55.