Mechanisms Underlying Oxytocin's Analgesia in Older Adults
Phase: PHASE2
Conditions: Knee Osteoarthritis, Osteoarthritis
Sponsor: University of Florida

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Protocol:  IRB201801467 (UCOPE Study) 
 
IRB version: 10/1/2018 
PI version: 05/10/2024 
UCOPE Protocol 
 
1. Project Title 
 
Mechanisms of Oxytocin’s Analgesia in Older Adults (Short title: UCOPE Study: Understanding 
Cognition, Oxytocin, and Pain in Elders) 
 
 
2. Investigator(s) 
 
Dr. Yenisel Cruz-Almeida (PI) 
Dr. Natalie C. Ebner (co-PI) 
Dr. Roger Fillingim (co-I) 
Dr. Roland Staud (co-I) 
Dr. Zhiguang Huo (co-I) 
 
3. Abstract 
 
Osteoarthritis (OA) represents a significant cause of disability worldwide in individuals aged 65 and 
older, a rapidly growing segment of our population. The knee is the most commonly affected joint with 
pain being the primary symptom, negatively impacting physical, cognitive, and emotional functioning. 
Symptomatic knee OA has been traditionally attributed to peripheral mechanisms, but measures of joint 
damage only modestly account for the presence or severity of OA-related pain. The neuropeptide 
oxytocin (OT) has been recognized as a mediator of endogenous analgesia in animal and human 
studies. However, little is known about the neurobiological mechanisms underlying OT’s pain-relieving 
properties. This proposal is based on a mechanistic model of OT’s analgesic effects leveraging pilot 
data supporting efficacy and safety of self-administered intranasal OT over 4-weeks in older individuals. 
Relative to placebo (P), daily administration of intranasal OT diminished self-reported pain intensity, 
reduced experimental pain sensitivity, and increased self-reported physical and emotional functioning. 
Further, participants treated with OT, compared to P, showed decreases in brain metabolite 
concentrations associated with inflammation. Thus, our overarching goal is to evaluate the effects of 
intranasal OT on pain and function in aging and to determine the extent to which central and peripheral 
inflammatory mechanisms contribute to these analgesic responses. We aim to 1) determine the effect 
of intranasal OT administration on clinical and experimental pain sensitivity in older adults with 
symptomatic knee OA and 2) characterize inflammatory mechanisms contributing to the inter-individual 
variability in analgesic responses to OT. Older adults with symptomatic knee OA will self-administer 
intranasal OT or P over 4 weeks using a double-blinded, cross-over study design. With strong support 
from the University of Florida and the McKnight Brain Institute, our interdisciplinary project, using a 
comprehensive multi-methods approach, will be the first to determine the potential benefit of OT as a 
novel analgesic therapy for knee OA pain in aging. OT is currently used in obstetrics and may be an 
inexpensive, effective method for pain management in older adults with little potential for addiction. 
Embedded in a biopsychosocial framework, our proposal will help pave the way for future investigations 
using a mechanism-based treatment optimization strategy for individuals suffering from chronic pain. 
 
4.  Background 
 
The prevalence and negative impact of chronic osteoarthritis pain among older adults is high: 
The burden of chronic pain among older adults is substantial with up to 60% of adults over 65 years 
reporting chronic pain in large community samples.28 Furthermore, older compared to younger adults 
are at a greater risk of developing chronic pain and experience greater pain intensity and pain at more 

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bodily sites.29,30 In particular, osteoarthritis (OA) is the leading cause of disability among older adults,1,2 
with the knee being the most commonly affected joint.3 Lifetime risk of developing symptomatic knee 
OA exceeds 40%, and OA prevalence in the U.S. population is rising due to increased age and 
obesity.31 With the number of adults aged over 65 years expected to double from 40 to 88 million by 
the year 2050, health concerns related to OA for older individuals and society at large will increase in 
the coming decades. This demographic encompasses a large and growing group in need of better 
therapeutic modalities that are based on mechanistic translational research. In particular, there is an 
urgent need to develop better analgesics for individuals with OA-related pain, since currently used 
analgesics frequently fail to provide adequate relief or have to be discontinued owing to adverse 
effects.32 
Pain associated with OA is heterogeneous: Historically, OA has been conceptualized as a regional 
pain condition with symptoms driven by peripheral pathophysiology. However, a growing body of 
evidence supports the notion that both local and low-grade systemic inflammation contribute not only 
to articular damage in OA, but also to pain and reduced physical function.33-36 The poor correspondence 
between measures of disease severity and clinical symptoms suggests that factors above and beyond 
peripheral tissue damage must contribute to OA-related pain.9 Indeed, recent studies demonstrate 
widespread abnormalities in brain structure and function in persons with symptomatic OA,37-40 including 
greater levels of metabolites associated with brain inflammation.41 Quantitative sensory testing (QST) 
findings also demonstrate a maladaptive pain-modulatory profile in symptomatic knee OA,11,42,43 
characterized by heightened pain facilitation and impaired pain inhibition, consistent with significant 
changes in pain processing at multiple levels of the neural axis (i.e., brain and spinal cord). 
Furthermore, individuals with severe knee OA pain experience significant maladaptive psychological 
characteristics consistent with changes in brain regions 
associated with mood and emotional function.5,39,44 
Oxytocin as a multifunctional analgesic targeting 
altered central and peripheral pain mechanisms in  
older adults with OA: A promising treatment candidate 
for pain that is increasingly discussed in the literature, is 
the neuropeptide oxytocin (OT).13,14 While best known 
for its roles in parturition and lactation,45 OT has been 
shown to play a role in endogenous analgesia with 
animal 
studies 
demonstrating 
anti-nociceptive 
effects.46-48 In humans, low plasma OT levels are 
associated with increased prevalence of chronic pain,15-
17 
and 
acute 
(i.e., 
one-time) 
intranasal 
OT 
administration decreases experimental pain sensitivity, 
increases pain inhibition, and improves mood and 
positive affect in younger inidividuals.18,19 However, the 
analgesic effects of chronic OT administration remain 
understudied in persons with chronic pain, and in 
particular, in older adults affected by symptomatic knee OA. The proposed work will address this 
research gap.  
A notable characteristic of OT is that it is multifunctional in ways that may be leveraged therapeutically.14 
OT’s potential analgesic mechanisms may be explained by its roles as both a neurotransmitter and a 
paracrine hormone (Figure 1). As a neurotransmitter, OT may provide analgesia via widespread effects 
on the brain22,26 and spinal cord.22  As a hormone, OT is released into the peripheral circulation and 
acts directly on multiple organ systems. Possibly connecting these two routes, the OT-secreting system 

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within the hypothalamus integrates neural, endocrine, and immune function.26 Indeed, animal studies 
suggest that OT can inhibit inflammation both in the brain and spinal cord,22 with recent evidence 
supporting that OT’s effect on inflammation may contribute to its analgesia. Similarly, in humans, OT 
decreases pro-inflammatory cytokines in the peripheral circulation,23 and our preliminary data 
implicates both peripheral and central inflammatory processes in OT’s analgesia. 
Further, OT’s effects in mood and affect regulation are likely explained by its interaction with the 
hypothalamic-pituitary-adrenal (HPA) axis and effects on stress regulation.26,49,50 Based on this 
combined evidence, our working hypothesis is that older adults with chronic knee OA may benefit 
therapeutically from OT’s multiple pain-modulatory mechanisms. 
 
5. Specific Aims 
 
Specific Aim 1: To determine the effect of intranasal OT administration on clinical and 
experimental pain in older adults with symptomatic knee OA. We will assess self-reported pain 
along with a standardized, multimodal experimental pain battery, and plasma levels of OT as modifier 
of a significant treatment response. We will also assess physical, cognitive, and emotional functioning. 
Informed by our pilot data, we hypothesize that compared to P, OT treatment will result in significant 
reduction in: H1a) self-reported pain intensity; H1b) experimental pain sensitivity; and increase in H1c) 
physical, H1d) cognitive, and H1e) emotional functioning assessed with self-reported and performance-
based measures. 
Specific Aim 2: To characterize inflammatory mechanisms contributing to the inter-individual 
variability in analgesic response to OT. We will assess central and peripheral inflammatory 
processes using proton MRS in frontal brain regions and plasma immune markers, respectively. Based 
on our preliminary data, we hypothesize that compared to P, OT administration will result in significant: 
H2a) decrease in plasma levels of IL-6, TNF-α, and IL-10; and H2b) decrease in brain metabolite 
concentrations associated with inflammation (i.e., MI, Cr, Cho). Further, H2c) decrease in brain 
metabolites and systemic cytokines will be significantly associated with decrease in clinical pain 
intensity. Other markers of brain structure and function will also be significantly associated with changes 
in clinical pain intensity (H2d). 
Exploratory Aim 3: To characterize effects of acute intranasal OT administration on clinical and 
experimental pain as well as underlying neurobiological mechanisms in younger and older 
controls. We will perform similar experiments as above in control participants to further understand 
OT’s analgesic effects across the lifespan in the absence of knee OA pain. However, acute OT 
administration will be used in healthy controls versus chronic administration in the presence of Knee 
OA.  
 
6. Research Plan 
We propose a double-blinded, randomized cross-over design that will randomize older adults with 
symptomatic knee OA pain and/or back pain to four weeks of intranasal self-administration of either OT 
or P (48 IUs daily) followed by a four-week washout period and a second four weeks of intervention 
(either OT or P). Our study design was guided by recommendations by the IMMPACT group for clinical 
pain trials.74-77  After initial screening, eligible participants will undergo up to four baseline sessions 
(health, sensory, and neuroimaging) for collection of clinical, functional (physical, cognitive, emotional), 
QST, and brain imaging data lasting 2-3 hours. At some point during the baseline, intervention, and 
post-intervention periods, participants may wear a Samsung Gear S® or Apple smartwatch or Oura ring 
to obtain daily pain, mood, and social activity assessments and to objectively measure physical activity 
levels and sleep quality. During the intervention, participants will self-administer twice daily 24 IUs 

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intranasal OT or P and will be contacted once a week for assessment of adverse effects and for 
download of the smartwatch/ring data. As in our pilot study, during the last week of each intervention 
period, up to four assessment sessions will follow that will be identical to the baseline sessions. On the 
mornings of assessment days, participants will not apply the OT/P nasal spray, to avoid confounding 
of acute and chronic effects.  
To increase flexibility and reduce participant burden, portions of the study (including the ICF) may be 
conducted remotely via phone calls, UF Zoom and/or online (RedCap). Parts of the study that cannot 
be conducted remotely, will be conducted in a single visit pre- and post- the intervention period and as 
needed study portions may be dropped. These portions include but are not limited to: blood draw and 
urine sample, Neuroimaging, sensory testing, and questionnaires. Questionnaires and /or surveys with 
sensitive questions, such as childhood trauma or suicidal ideations, will continue to be administered in 
person. 
Participants: Based on power-analytic considerations, we plan to enroll a total of 160 individuals of 
both sexes (approx. 50% male) from various ethnicities. This sample size includes a 20% attrition rate. 
Older adults over 45 years of age who meet American College of Rheumatology clinical criteria for 
knee OA78 and/ or back pain of at least six months duration, experience pain on more days than not, 
with moderate pain at baseline (i.e., > 3/6 in the VDS), and who have elevated levels of plasma IL-6 
(>2.5 pg/ml) will be considered for participation. We will also recruit 160 control individuals (80 older 
adults over 45 years of age without knee osteoarthritis pain and 80 younger controls 18 to 30 years of 
age). Both community-based and clinic-based recruitment methods established in our labs will be 
utilized. We will also utilize IRB approved registries to contact potential participants.  
Exclusion criteria will align with study and safety requirements related to: 1) OT application 
[hypersensitivity to OT or vasopressin, history of hyponatremia, syndrome of inappropriate antidiuretic 
hormone secretion, or psychogenic polydipsia, on vasoconstrictors such as desmopressin, 
pseudoephedrine, or antidiuretic medication, or anti-inflammatory drugs, or muscle relaxants, low 
sodium and high osmolality levels, blurred vision caused by a medical condition, excessive smoking, 
excessive drinking, muscle pain as a result of systemic disease, significant nasal pathology, previous 
or concurrent use of narcotics delivered intranasally (e.g., cocaine), or gastroparesis. If a participant 
has both low sodium (<134mEq/L) and high osmolality (>1200L), we will conduct a second blood test. 
If the sodium is again low (<134mEq/L) in the repeat blood draw, the participant will be excluded. Given 
that myocardial OT receptors,79 when bound to, inhibit cardiovascular activity,80 individuals with heart 
problems (e.g., cardiomyopathy, history of myocardial infarction, arrhythmias, prolonged QT interval) , 
and any form of cardiac surgery will be excluded]. Results of blood or/and urine testing may indicate that 
the participant should not participate in the study (e.g., certain test results could be out of normal 
range). If this is the case, we will give the participant a copy of your lab results, so that the participant 
may share them with the participant’s own medical provider and seek care if appropriate. 
2) Pain testing [participants will be excluded if they have concurrent medical or arthritic conditions that 
could confound symptomatic knee OA-related outcomes or coexisting disease that could preclude 
successful completion of the protocol including: systemic rheumatic condition (e.g. rheumatoid arthritis, 
systemic lupus erythematosus, fibromyalgia); a history of clinically significant surgery to the index knee; 
uncontrolled hypertension (>150/95); poorly controlled diabetes (HbA1c>7%); cardiovascular or 
peripheral arterial disease; serious psychiatric disorder requiring hospitalization within the past twelve 
months or characterized by active suicidal ideation; diminished cognitive function that would interfere 
with completion of study procedures (i.e., unable to understand instructions )];81 and 3) MRI/MRS [large 
pieces of metal in the body or metal in the face or neck, claustrophobia, major medical surgery in the 
past two months, history of brain surgery or any serious brain condition like aneurysm, stroke, or 

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seizures]; and 4) pregnant individuals will be excluded; and 5) enrolled in another interventional 
research study.  
Initial screening: After phone consent, all potential participants will undergo an initial screening 
interview, via telephone or in-person depending on the recruitment setting (Figure 7). This screening 
procedure will include a knee OA screening interview that has shown 87% specificity and 92% 
sensitivity for detecting knee OA.82 This interview includes four questions regarding knee pain and 
swelling and previous diagnosis of knee OA. The initial screening will also assess MRI eligibility, age, 
gender, handedness, and additional health history information, and demographic information such as 
education level, household size and race/ethnicity for sample descriptive purposes. The Telephone 
Interview for Cognitive Status (TICS) will be given to participants to assess cognitive status. Eligible 
individuals will be scheduled for the Health Assessment Session. All participants will undergo the same 
procedures as described below, but control subjects will have the option to participate in acute (i.e., 
same day) oxytocin/placebo administration. If a control participant does not wish to undergo the spray 
administration, they would complete all other aspects of the visits. If control participants wish to undergo 
the spray administration, this will occur the same day as the neuroimaging visit (i.e., acute 
administration).  
 
Phase One Procedures for Knee OA Participants: 
Health Assessment Visits (Pre/Post) 
Saliva, Urine and blood samples. After written informed 
consent, participants will provide a urine sample to determine 
osmolality and a fasting blood sample to evaluate standard 
clinical parameters (Comprehensive Metabolic Panel (CMP-14) 
Blood Test), which will be reviewed by Co-I Staud to determine 
study continuation. Following established pilot study procedures, 
blood samples will also be used for determination of plasma 
neuropeptide 
(e.g., 
OT, 
arginine 
vasopressin 
(AVP)) 
concentrations and inflammatory markers (e.g., IL-6, TNF-α, C-
reactive protein (CRP)); as well as genetic markers associated 
with OT. This session will take place in the mornings to 
accommodate for fasting and to control for circadian fluctuations. 
For women under the age of 62, pregnancy tests will be 
conducted at study start. Samples may be collected during any 
session that is most convenient for the participants as long as 
this is collected before randomization. Saliva samples will be 
collected for additional DNA testing on genetic markers 
associated with OT. Saliva collection has been done previously 
for the study of OT and other hormones in the body.  
Physical examination. Height and weight will be measured and 
Body Mass Index (BMI) will be calculated as it is significantly related to pain symptoms in OA.83 
Participants will complete a thorough Pain and Medical History Questionnaire, including a review of 
bodily systems assessing the reported duration of OA, current and past treatments for OA, comorbid 
conditions, baseline adverse events reporting, and current medication use as in our previous knee OA 
studies.5,57 Information regarding hormone replacement therapy will be obtained for both sexes, and 
for women, information regarding menopausal status, as this may interact with baseline OT levels and 
OT intervention effects.84 If there are concerns with eligibility, participants will undergo a Physical 

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Examination by the study rheumatologist (Co-I Staud) to: 1) confirm the diagnosis of knee OA according 
to ACR clinical and radiographic criteria;78 2) rule out any exclusion criteria; and 3) identify the most 
symptomatic knee. Manual examination of joint tenderness may be performed bilaterally for hands, 
hips, and knees. Symptomatic hip OA is common in the knee OA population85-87 and is associated with 
disability87 and thus will be included as a covariate.  
Clinical pain will be assessed according to location, overall pain severity, and pain interference with 
daily activities. These measurements will encompass the key dimensions for pain assessment as 
recommended by the American Geriatrics Society88 and according to the pain taxonomy by the 
Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and 
Networks and the American Pain Society group (AAPT).89,90 A Verbal Descriptor Scale (VDS) will 
assess changes in pain intensity before and after treatment. The VDS has anchors of “No pain” (scored 
as 0) and “The most intense pain imaginable” (scored as 6) and is easier to understand and preferred 
over numerical rating scales by older individuals,67 and has been effectively utilized in our pilot study. 
We will also administer the Western Ontario and McMaster Universities Osteoarthritis Index 
(WOMAC),91 a reliable, well-validated measure of lower extremity pain and function in individuals with 
knee OA. Summary scores of the WOMAC range from 0 (No pain or disability) to 96 (Extreme pain or 
disability).  
Knee x-ray. Weight-bearing radiographs will be taken for all participants. Co-I Staud will determine the 
Kellgren-Lawrence (KL) score and indicate which compartment(s) are affected in each knee (medial, 
lateral, patellofemoral) to determine study continuation. KL scores will be assessed in a blinded manner. 
This is only done at the baseline visit.  
Real-time assessment of pain and mobility. At some point during the baseline sessions, participants 
may be trained by study staff in the use of the Samsung Gear S® or Apple smartwatch or Oura Ring. 
Participants will also be given a guidebook explaining how to use the smartwatch/ring. Traditional self-
report measures of pain cannot capture real-time data under naturalistic conditions or measure 
fluctuations on a daily or hourly basis. The UF Institute of Aging Data Science and Applied Technology 
(DSAT) Core has recently validated the use of electronic data capture by the Samsung Gear S® or 
Apple smartwatch to measure pain, mood, mobility, and other outcomes in older adults.92,93 The DSAT 
Core infrastructure includes a secure smart watch app which summarizes sensor-monitored data (e.g., 
tri-axial accelerometer, GPS location) and a graphical interface allowing ecological momentary pain, 
mood and social activity assessments through a turn dial bezel (Figure 8). Data collection on smart 
watches offers several advantages 
including 
capability 
of 
long-term 
continuous data collection, ecological 
validity, 
cost 
effectiveness, 
and 
convenience 
and 
low 
participant 
burden. “Momentary” pain intensity will 
be captured randomly four times per 
day throughout the study. Data will be 
downloaded remotely or when the 
individual reports to the clinic during the 
intervention phase. Participants will 
start wearing the device during the baseline weeks and at each visit their proficiency and use will be 
ascertained. Data extraction and analysis will be performed by the DSAT Core. 
Sensory Assessment Visits (Pre/Post) 

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Pain and psychosocial questionnaires. We will also administer the West Haven Yale 
Multidimensional Pain Inventory providing well-validated measures of several important dimensions of 
the chronic pain experience. Multiple psychosocial factors have been related to chronic pain. We will 
assess psychosocial factors across the following broad domains. 1) Pain coping: The Coping 
Strategies Questionnaire-Revised (CSQ-R)94 consists of 27 items relating to how individuals cope with 
pain. It comprises six subscales based on pain coping strategies that individuals report (i.e., diverting 
attention, catastrophizing, praying and hoping, ignoring pain sensations, reinterpreting pain sensations, 
and coping self-statements). 2) Affective distress: The Beck Depression Inventory, 2nd Edition95 is a 
widely used depression scale that assesses affective (e.g., sadness, loss of interest), cognitive (e.g., 
worthlessness, guilty feelings), and somatic (e.g., changes in sleep, tiredness or fatigue) symptoms 
common amongst depressed individuals. It contains 21 self-report items assessing the frequency and 
severity of depressive symptoms over the previous two weeks.  
Since item # 9 from the Beck Depression Inventory refers to suicidality, the experimenter will, before 
the end of the test session, review the participant's 
response to this item, and if the participant has 
chosen response option 2 = “I would like to kill 
myself “or 3 = “I would kill myself if I had the 
chance”, the experimenter will contact the PIs 
immediately and the PIs or their designee will 
contact Dr. Dawn Bowers (or her designee) at the 
University of Florida Psychology Clinic (352-265-
0294) who will make recommendations. In the 
unexpected event that the clinic personnel are not 
available, the Alachua County Crisis Center will be 
contacted. 
The 
same 
procedure 
will 
be 
implemented for the post-intervention assessment. 
The Positive and Negative Affect Scale (PANAS) 
is a 20-item scale that assesses positive and 
negative affect.96 The PANAS has demonstrated 
adequate reliability and validity.97 For this study, 
participants will be requested to provide “state” 
information by responding to items “at the present 
moment.” 3) Satisfaction/quality of life: We will 
assess self-reported quality of life using the 36-
Item SF Survey Quality of Life98 consistent with our 
pilot study, while the Satisfaction with Life Scale 
(SWLS)99 will assess satisfaction with people's 
lives as a whole. 4) Sleep and Food Recall: Self-reported sleep quality during the past month will be 
measured using the Pittsburgh Sleep Quality Index (PSQI).100 We will also ask participants to report 
what they ate the previous 24 hours. 5) Interoceptive awareness: We will assess self-reported 
interoceptive awareness using the multidimensional assessment of interoceptive awareness (MAIA)114 
6) Chronic Stress: Using the Daily Stress Inventory, we will collect participants’ self-reported daily 
assessment of the sources and individualized impact of relatively minor stressful events.11520 7) 
Perceived Stress Scale: Participants fill out a self-report assessment of their thoughts and feelings 
during the last month.116 8) Impulsivity: We will assess self-reported behavioral inhibition using the 
Behavioral Inhibition System and Behavioral Activation System (BIS/BAS) scales.117 9) Neuropathy: 
Individuals will respond to the PainDetect questionnaire to assess neuropathic pain detection. If an 
individual scores greater than 12, their clinical pain for each area of testing will be assess during the 

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quantitative sensory testing session.118 10) Empathy: We will assess empathy using the Affective and 
Cognitive Measure of Empathy (ACME) questionnaire.119 11) Back Pain: If an individual indicates they 
experience back pain, we will assess such pain using the Chronic Low-Back Pain (Minimal Dataset)120, 
Oswestry Low Back Pain Disability Questionnaire121, and Brief Pain Inventory122 questionnaires. 12) 
Early Trauma: Individuals will respond to the Childhood trauma questionnaire-short form (CTQ-SF)123, 
the Adverse and Traumatic Experiences Scale124 and the Brief Resilient Coping Scale.125 13) 
Aggression: Individuals will respond to the State-trait Anger Expression Inventory-2 (STAXI-2)126, 
Cohen-Mansgield Agitation Inventory (CMAI) aggressive behavior subscale (CMAI-ABS)127 and the 
Ryden Aggression Scale (RAS) physically aggressive behavior subscale (RAS-PABS)127. 
Quantitative Sensory Testing (QST). Participants will undergo QST to determine responses to 
mechanical and thermal stimuli and conditioned pain modulation (CPM) (Figure 9; see also5,12,101). We 
will randomize the order of thermal and mechanical testing. Cold pressor assessment, including 
conditioned pain modulation, will always occur last to avoid carryover effects. Patients’ medications 
and current clinical pain will also be confirmed.  
Mechanical testing procedures. Pressure pain threshold (PPT) will be assessed at the medial and 
lateral joint lines of the index knee, and at the ipsilateral quadriceps and trapezius muscles. For all PPT 
measurements, after an initial practice trial, three trials will be conducted and their average will be 
computed for data analysis. Using a digital, handheld, clinical grade pressure algometer (Algomed, 
Medoc, Ramat Yishai, Israel), the examiner will apply a constant rate (30 kPa/second) of pressure and 
the participant will press a button when the sensation first becomes painful, at which time the device 
records the pressure. Punctate Mechanical Pain will be assessed at the patella of the index knee and 
the dorsal aspect of the ipsilateral hand using a nylon monofilament (Touchtest Sensory Evaluator 6.65) 
calibrated to bend at 300g of pressure. As in our previous studies,5,12,57 participants will provide a pain 
rating following a single contact, after which they will provide another pain rating following a series of 
ten contacts at a rate of one contact per second. The difference between the pain rating for the single 
versus multiple contacts reflects temporal summation of mechanical pain. 
Thermal testing procedures. Thermal stimuli will be delivered to the (most) affected knee and/or to 
the ipsilateral forearm and/or thenar eminence, in randomized order, using a Medoc Pathway Thermal 
Sensory Analyzer (Ramat Yishai, Israel). Heat pain threshold will be assessed at each site, followed 
by heat pain tolerance and temporal summation. Heat pain thresholds and tolerances will be assessed 
using an ascending method of limits as in previous studies.5,12,57 Temporal summation of thermal pain 
will be assessed using the same stimulus parameters as previously reported by us and others.5,12,57 To 
measure Cold Pressor Pain, a modified cold-pressor procedure will be conducted. Each participant will 
complete a series of 60-second immersions in cold water baths at 10ºC, with water temperature 
maintained (±0.1ºC) by a refrigeration unit. Participants will immerse their left hand up to the wrist with 
their fingers spread apart. Participants will report when they first feel pain, and this time point will be 
recorded as the pain threshold. Then, they will continue for one minute or until they report intolerable 
pain. If a participant terminates early, the time at which they terminate will be recorded as pain 
tolerance. Participants will be prompted to rate the intensity of the cold-pressor pain at 30-sec intervals.  
Conditioned Pain Modulation (CPM) will be used to assess pain-inhibitory function. The conditioning 
stimulus will be the cold pressor task applied to the left hand, which will be tailored for each participant 
to achieve a stimulus that produces moderate pain (i.e., a rating of 40-60 on the 0-100 scale) and can 
be tolerated for a 60-second period. The test stimulus will be heat pain applied to the opposite ventral 
forearm, at a stimulus intensity which produces moderate but tolerable pain. First, baseline heat pain 
responses will be assessed, after which the participant will immerse their hand in the cold water bath 
for 60 seconds. Immediately afterwards the heat pain will again be applied to the opposite arm and pain 
ratings will be obtained.  

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Short Physical Performance Battery (SPPB) and Mobility Assessment. As a performance-based 
indicator of OT’s effect on function we will use this brief assessment consisting of four lower-extremity 
function measures: standing, balance, walking speed, and ability to rise from a chair. These measures 
have been standardized and are widely used in older populations and have been used in our own 
labs.102,103 We will also measure movement-evoked pain during each task which is associated with 
central pain processing in knee OA.103 Participants will also be asked to undergo a number of mobility 
assessments. Participants will be asked to walk over a mat without any obstacles, as well as stepping 
over an obstacle, and while performing a cognitive task. Some tests will be performed while walking 
over an instrumented walkway, which measures spatiotemporal gait parameters. 
Neuroimaging Assessment Visits (Pre/Post) 
Cognitive battery. Previous studies including those from PI Ebner support OT’s role in cognition,65,84, 
while those from PI Cruz-Almeida implicates decreased cognitive function in older adults with chronic 
pain.128-130 Given our preliminary findings of changes in metabolites in the frontal cortex, assessment 
of executive function is particularly warranted. Cognitive performance will be assessed via the NIH 
Toolbox (www.nihtoolbox.org).104 This battery comprises measures of executive function, attention, 
episodic memory, language, processing speed, and working memory. Following NIH scoring 
guidelines, administering this battery will yield the Cognitive Function Composite Score and the 
Crystallized Cognition Composite Score (e.g., Picture Vocabulary and Reading Recognition), in 
addition to subtest scores. We will also administer the Montreal Cognitive Assessment (MoCA) as in 
our previous work.128 
Neuroimaging (up to 2 visits each time). Participants will lay supine in the MRI magnet for up to 2 
hours and fill out a post event questionnaire at the conclusion of the scan. We will use a state-of-the-
art 3T Siemens Prisma MR system at the McKnight Brain Institute (MBI) for collecting anatomical, 
structural, functional, and biochemical scans. Anatomical image acquisition will involve a T1-weighted 
structural scan using a magnetization-prepared rapid gradient echo (MPRAGE) sequence, and a T2 
FLAIR scan, which provides good contrast between gray and white matter, and cerebrospinal fluid 
based on tissue T1 and T2 differences. Functional scans (fMRI) will be taken while the participant is 
resting quietly, completing a cognitive task and while painful stimulation is being applied using a  (MRI-
compatible) heat thermode routinely used in neurological examinations. We will also acquire single-
voxel MEGA-PRESS water-suppressed 1H spectra with water T2 measurement. A simple visual task 
will also be performed to control for non-specific cognitive influences. Brain MRI data will be used to 
measure the structural and functional integrity of the brain including, but not limited to, descending 
sensory and motor tract integrity (fiber tractography), intracranial volume, whole brain volume, lacunae 
as well as metabolite concentrations.  
fMRI data analysis. We will use the same stages for functional connectivity analysis as prior work12,13 
using Freesurfer (http://surfer.nmr.mgh.harvard.edu/) and AFNI (http://afni.nimh.nih.gov/afni). Seed 
regions will be placed in areas that include prefrontal, striatal and insular regions. To calculate the time 
series of the region of interest (ROI), a sphere with a radius of 3.5mm will be placed in the structure of 
interest (based on an MNI template). An inverse transform derived from the anatomical scan will be 
applied to transform the ROI from MNI common space into subject space. The mean signal of non-zero 
voxels within the ROI will be calculated. Pearson correlation maps will be created by correlating time 
series in a seed region to residual time series in each voxel of the brain. The maps are then converted 
to a z-score via a Fisher tanh-1 transform in order to perform a group analysis and z-score maps are 
transformed into MNI space via transforms derived from warping the anatomical scans.  
dMRI data analysis. We will use FSL (http://www.fmrib.ox.ac.uk/fsl). A 3D affine registration will be 
applied to each diffusion weighted scan to correct for head motion and image distortions and a binary 
mask will be created to mask the brain and avoid the skull. Bayesian estimation will be used to calculate 

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a probability distribution of fiber directions for each voxel21, allowing estimates of two directions per 
voxel12. Using the preprocessed data, probabilistic tractography will be used to identify probable fiber 
tracts between a seed region and a waypoint.  Each voxel within the seed will have a fiber leaving it, 
and the probable fiber tracts will be traced between the seed voxel and waypoint. From all voxels within 
the seed mask, the tractography algorithm generates 5000 streamline samples, with a step length of 
0.5mm and a curvature threshold of 0.2. These samples are computed through the probability estimate 
on fiber direction at each voxel. The conjunction of these 5000 paths will then calculated. Higher values 
reflect a greater probability that the voxel is part of the tract between the seed and waypoint with a 
distance correction. The voxel with the highest value will be identified in each tract and 1% of this value 
will be used as the threshold value to remove voxels. Analysis will be restricted to voxels within the 
white matter using individual’s gray matter masks derived from each T1-weighted image. Masks will be 
generated with FreeSurfer’s automated tools for segmentation. Integrity measures will then be 
extracted from each fiber tract mask.  For spatial normalization we will use DTI-TK. DTI-TK is a non-
parametric, diffeomorphic deformable image registration that incrementally estimates its displacement 
field using a tensor-based registration formulation. It is designed to take advantage of similarity 
measures comparing whole tensors via explicit optimization of tensor reorientation13.  
Magnetic Resonance Spectroscopy (MRS): A non-invasive, non-ionizing radiation technique that 
uses proton signals to determine the relative concentrations of target brain metabolites. The GABA-
edited spectra will be acquired using a MEGA-PRESS sequence, TE 68ms; TR 2s; 14ms sinc-Gaussian 
editing pulses applied at 1.9 ppm (ON) and 7.56 (OFF); VAPOR water suppression; 10 min duration). 
Spectra will be analyzed using the Gannet package for the batch analysis of GABA-edited MR spectra, 
quantifying GABA concentration relative to water, correcting for voxel CSF fraction. OFF spectra will 
be analyzed using LCModel to give concentrations for additional metabolites NAA, Glx, Cho, MI, and 
Cr. Assurance: GABA-edited MR spectra will be visually screened, and spectra with a fitting residual of 
over 10% will be accepted for further analysis. The concentration measures for the additional 
metabolites will be accepted with an LCModel Cramer-Rao lower bounds (%SD) of less than 20%, a 
reliable estimate for a given metabolite for group comparisons. 
In general, questionnaires and testing may be collected during any session that is most convenient for 
the participants as long as all the data is collected before randomization to intervention. Participants will 
also be allowed to complete any of the assessments during extra visits to reduce their burden and avoid 
participant fatigue. All sessions will begin with an intake interview regarding events that occurred during 
the past 24 hours.  
Intervention period for Knee OA Participants  
During the 4-week intervention, participants will self-administer via intranasal spray 24 IUs of OT or P 
twice a day at home, at 8-9AM and again at 5-6PM. Participants that take any other nasal spray, will 
be asked to separate sprays by 20 minutes and this will be recorded in the diary. Missed doses will not 
be a deviation and participants are instructed to log each day whether they took the spray or not. The 
utilized synthetic OT is a formulation developed in Dr. Feifel’s lab at UCSD (IND #100,860; see letter 
of support from Dr. Feifel and IND letter). Dr. Ebner has been sub-investigator on this IND for several 
years.49,105 The drug (i.e., synthetic OT) and the P (i.e., containing all of the inert ingredients except for 
the OT) will be compounded at UF’s Investigational Drug Services (IDS). Dr. Ebner has established 
this compounding route together with Dr. Susan Beltz, chief pharmacist at UF IDS under Dr. Feifel’s 
protocol and successfully and safely implemented procedures in our pilot study. Compliance will be 
monitored by measuring the fluid left in the spray bottle after the treatment period and using a log that 
participants fill in each day during the intervention. If any time during the treatment it is determined that 
the participant should not continue due to adverse events, the participant will be discontinued. 
Furthermore, at baseline and at the end of the intervention, blood and urine samples will be checked 

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(e.g., for osmolality levels, sodium levels, and any other blood markers out of range) to ensure that no 
adverse changes have occurred during the study intervention. Additionally, before and after the 
intervention period participant will fill out the Goal Attainment Scale (GAS). For the majority of the 4-
week intervention periods, participants may complete daily assessments via their Samsung Gear S® or 
Apple smartwatch or Oura Ring. We will be able to assess pain, mood, and activities at random times 
throughout the day. Participants will be contacted once a week to assess side effects and asked if they 
have been completing their diaries. Any symptom reported as moderate or severe will be brought to 
the PIs' attention and will be discussed with the study MD as needed on a case by case basis. These 
weekly calls will also ensure regimen compliance and will assist participants in download of the 
Samsung Gear S® or Apple smartwatch or Oura Ring data to a secure research server. We have 
successfully established a similar approach in other projects within our institute, and the DSAT Core 
has validated pipelines for data analysis.92,106  
Post-Intervention Assessments for Knee OA Participants 
In the last week of the intervention, participants will be scheduled to return for up to four (or 6 with the 
MRI) post-intervention visits, which will be identical (with minor exceptions) to the baseline visits. 
Importantly, at the follow-up Health Assessment we will assess changes in health status, and their 
global impression of change (PGIC/MPIC) since starting the intervention. 
Wash-out Period for Knee OA Participants 
Participants will undergo a four-week wash-out period in between phases one and two. The wash-out 
period will serve to prevent confounding variables between both drug administrations. Four weeks is a 
sufficient period of time for participants to return to baseline levels prior to drug administration. 
Phase Two Procedures for Knee OA Participants 
After the four-week wash-out period, participants will enter phase two of the study. Phase Two is 
completely identical to Phase One: up to 4 (or 6 with the MRI) Baseline Visits, Intervention Period, and 
up to 4 (or 6 with the MRI) Post-Intervention Visits. Participants will be given the other drug from the 
first intervention period per randomization.  
At study closure, participants will also be asked to guess what study medication they were taking in 
order to assess the effectiveness of blinding, followed by a full debriefing regarding the study aims and 
a study post event questionnaire. Our pilot data suggest that participants are unaware of their assigned 
treatment condition. We will implement several strategies to enhance retention, and based on our pilot 
data, we anticipate high success in completing all follow-up visits in at least 90% of our sample. Finally, 
one week, three months and at 6 months after the last treatment phase, participants will receive a 
follow-up phone call to determine if any side effects occurred, as well as answer the WOMAC and 
PANAS to inquire about pain. All study participants will be financially compensated for study 
participation. During these calls, if symptoms that indicate imminent danger to the participant are 
reported such as light headedness, fainting, heart changes, palpitations, shortness of breath, and 
abdominal pain, staff will immediately advise participants to contact emergency medical services. 
Simultaneously, this matter will be immediately escalated to study physician and PIs and the physician 
or his proxy will be in immediate contact with the participant to determine appropriate steps for follow-
up. 
Compensation 
We will compensate participants in the form of a pre-paid, reloadable VISA card issued by the 
University of Florida or by cash payments. Payments are broken down by visits ($75 per visit), the 
four week interventions ($75 for each intervention) and additional compensation for returning all study 

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materials ($75). The MRI portion of the study is optional, which would decrease the number of visits 
needed to attend for the entire study.  
Procedures for Control Participants: 
Health Assessment Visits 
Urine and blood samples. After written informed 
consent, if participants choose to take the 
OT/Placebo administration, control participants 
will provide a urine sample to determine osmolality 
and a fasting blood sample to evaluate standard 
clinical parameters (Comprehensive Metabolic 
Panel (CMP-14) Blood Test), which will be 
reviewed by Co-I Staud to determine study 
continuation. All control participants, regardless 
whether they will receive acute OT/Placebo will 
provide blood samples for determination of plasma 
neuropeptide (e.g., OT, arginine vasopressin 
(AVP)) concentrations and inflammatory markers 
(e.g., IL-6, TNF-α, C-reactive protein (CRP)); as 
well as epigenetic markers associated with OT. 
This session will take place in the mornings to 
accommodate for fasting and to control for 
circadian fluctuations. For women under the age 
of 62, pregnancy tests will be conducted at study 
start. 
Physical examination. Height and weight will be 
measured and Body Mass Index (BMI) will be 
calculated. Participants will complete a thorough Pain and Medical History Questionnaire, including 
current medication use. Information regarding hormone replacement therapy will be obtained for both 
sexes, and for women, information regarding menopausal status, as this may interact with OT levels 
and effects.84 
Cognitive battery. Participants will undergo the same cognitive testing procedures as the knee OA 
participants.  
Real-time assessment of pain and mobility. At some point during the baseline sessions, participants 
may be trained by study staff in the use of the Samsung Gear S® or Apple smartwatch or Oura Ring. 
Participants will also be given a guidebook explaining how to use the smartwatch/ring. Participants will 
wear the device during the baseline weeks. 
Sensory Assessment Visits 
Pain and psychosocial questionnaires. We will also administer the same questionnaires as in the 
knee OA participants to ascertain daily pain and emotional functioning. If control participants agree and 
consent to the OT/Placebo acute administration, they will also undergo these measures after the 
OT/Placebo administration. 
Quantitative Sensory Testing (QST). Participants will undergo the same QST procedures as the knee 
OA participants (Figure 9; see also5,12,101). If control participants agree and consent to the OT/Placebo 
acute administration, they will also undergo these measures after the OT/Placebo administration. 

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Short Physical Performance Battery (SPPB) and Mobility Assessment. Participants will undergo 
the same performance-based measures of function as the participants with knee OA. If control 
participants agree and consent to the OT/Placebo acute administration, they will also undergo these 
measures after the OT/Placebo administration. 
Neuroimaging. Participants will undergo the same procedures as the knee OA participants. Control 
participants that agree to take part in the OT/Placebo administration will undergo 2 MRIs, before and 
after OT/Placebo administration. 
OT/Placebo Acute Administration for Control Participants  
Control participants will self-administer one acute administration of OT or P, at 8-9AM if they have 
previously consented to this part of the study. At study closure, participants will also be asked to guess 
what study medication they took in order to assess the effectiveness of blinding, followed by a full 
debriefing regarding the study aims and a study post event questionnaire. Control participants will also 
be financially compensated for study participation.  
Sample assays: The OT neuropeptide assay will be conducted in Dr. Carter’s lab, using standard 
enzyme-linked immunosorbent assay (EIA) and LC Mass Spectrometry methods; in collaboration with 
the biochemical research company Martin Protean LLC. Although EIAs are typically highly sensitive, 
with minimum detection levels of 12pg/mL OT and very little antibody cross-reactivity with other 
neuropeptides, all samples will be run in duplicate. Dr. Carter and PI Ebner have been collaborating on 
sample assays over the past years.65,107 The immune assay will include inflammatory biomarkers (e.g., 
CRP, TNFa, IL-6) via immunoassay kits as in our previous studies.60,61,108 All samples will be measured 
in triplicate and the average of the three measures will be used for data analysis. Samples will be 
analyzed by the Institute on Aging Metabolism and Translational Science Core. The samples collected 
in the present study will only be used to answer questions about this study and will not be banked for 
future studies. 
 
Compensation for Control Participants 
We will compensate control participants with up to $330 upon study completion in the form of a pre-
paid, reloadable VISA card issued by the University of Florida or by cash payments. In particular, for 
completion of 
o Screening Visit, Baseline Visit: $75 
o Sensory Visit: $75 
o Neuroimaging Visits (up to 2 visits): $75 per visit 
o (Optional) extra $30 if you choose to participate in the nasal spray treatment. 
 
 
Power and sample size considerations: Based on our pilot study estimates, we plan to recruit 160 
participants, i.e., 80 participants in each of the randomly assigned treatment groups for the baseline 
visits. Assuming an attrition rate of 20% at the follow-up visits, we will have 128 participants (64 in the 
OT and 64 in the P group) at the 4-week post-intervention follow-up visits. This sample size yields a 
power over 0.80, even based on a very conservative Bonferroni correction for multiple comparisons 
(i.e., testing twelve hypotheses), which lowers the alpha level from α=0.05 to α=0.006. However, our 
proposed data-analytic strategy will use the Benjamini and Hochberg procedure to control for multiple 
comparisons, which is less stringent than the Bonferroni correction, and thus we expect the actual 
power to be larger than 0.80.  
Hypotheses and data-analytic strategy: We summarize all hypotheses and planned analyses in 
Table 3 for aims 1 and 2. The statistical analyses will be conducted by Co-I Huo (Biostatistician) in 

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collaboration with Dr. Wu (Consultant, Institute on Aging Biostatistics and Bioinformatics Core Leader, 
see letter of support) using R software. For studying the relationship between pre- to post-intervention 
(longitudinal) outcomes and predictors, we will fit linear mixed effects models (LMEMs) [1] with subject 
specific random effects to account for the within-subject correlation, by R function “lmer”.109 Baseline 
outcomes and covariates will be adjusted to take account for confounding effects. Below is the formula 
for the linear mixed effect model: 
 
𝑦𝑦𝑖𝑖𝑖𝑖= 𝜇𝜇+ 𝛼𝛼𝑖𝑖+ 𝛽𝛽𝛽𝛽(𝑧𝑧𝑖𝑖= 1) + ෍𝛾𝛾𝑙𝑙𝑥𝑥𝑖𝑖𝑖𝑖
𝐿𝐿
𝑙𝑙=0
+ 𝜂𝜂𝜂𝜂(𝑘𝑘= 2) + 𝜃𝜃𝜃𝜃(𝑧𝑧𝑖𝑖= 1, 𝑘𝑘= 2) + 𝜀𝜀𝑖𝑖𝑖𝑖, 𝛼𝛼𝑖𝑖~𝑁𝑁(0, 𝜎𝜎0
2), 𝜀𝜀𝑖𝑖𝑖𝑖~𝑁𝑁(0, 𝜎𝜎2) [1] 
where 𝑦𝑦𝑖𝑖𝑖𝑖 is the outcome variable (e.g., pain intensity/sensitivity/function for Aim 1) for subject 𝑖𝑖 and 
visit 𝑘𝑘 (𝑘𝑘= 1 for intervention and 𝑘𝑘= 2 for post-intervention); 𝜇𝜇 is the intercept term; 𝛼𝛼𝑖𝑖~𝑁𝑁(0, 𝜎𝜎0
2) is the 
random effect with variance term 𝜎𝜎0
2 for subject 𝑖𝑖; 𝑧𝑧𝑖𝑖 is the treatment indicator with 𝑧𝑧𝑖𝑖= 0 for P and 𝑧𝑧𝑖𝑖= 1 
for OT, 𝛽𝛽 is the treatment effect (OT effect compared to P effect) and 𝕀𝕀(. ) is the indicator function which 
equals 1 if the argument inside (. ) is true and equals 0 otherwise; 𝑥𝑥𝑖𝑖𝑖𝑖 is the 𝑙𝑙𝑡𝑡ℎ covariates for subject 𝑖𝑖 
with 𝑙𝑙= 0 for baseline level (e.g. baseline pain intensity before treatment for Aim 1) and 𝑙𝑙= 1,2, … , 𝐿𝐿 for 
𝐿𝐿 covariates (i.e., age, sex, race…); 𝜂𝜂 is the time effect of post-intervention visit compared to pre-
intervention visit; 𝜃𝜃 is the interaction effect between post-intervention and OT; 𝜀𝜀𝑖𝑖𝑖𝑖~𝑁𝑁(0, 𝜎𝜎2) is the error 
term with variance 𝜎𝜎2. From equation [1], we will test whether there is a significant OT effect for both 
intervention and post-intervention. LMEMs allow for missing data if missing-at-random (MAR).   
Table 3. Proposed hypotheses and planned analyses. 
Specific Aims  
Hypotheses 
Planned Analyses 
#1: Clinical and 
experimental 
pain  
  
H1a: OT vs. P administration 
will reduce self-reported pain 
intensity 
LMEMs*; DV: Clinical pain 
                IV: Treatment (OT/P) 
H1b: OT vs. P administration 
will decrease experimental pain 
sensitivity 
LMEMs*; DV: QST 
                IV: Treatment (OT/P) 
H1c-1e: OT vs. P administration 
will increase physical, cognitive 
and emotional function 
LMEMs*; DV: SPPB, Exe. Function, 
Catastrophizing 
                IV: Treatment (OT/P) 
#2: Inflammatory 
mechanisms 
  
H2a: OT vs. P will decrease 
systemic inflammation 
LMEMs*; DV: Plasma cytokines (IL6, TNFα, 
IL10) 
                IV: Treatment (OT/P) 
H2b: OT vs. P will decrease 
brain metabolite concentrations 
associated with 
neuroinflammation 
LMEMs*; DV: Brain metabolites (tCr, MI, 
Cho) 
                IV: Treatment (OT/P) 
H2c: Decrease in brain 
metabolites and systemic 
cytokines will be associated with 
decrease in clinical pain 
Correlations/ Regressions             
IV: Decrease in brain metabolites 
and systemic cytokines  
DV: Decrease in clinical pain 
Note. IV = Independent variable; DV = Dependent variable; LMEMs: linear mixed effects models; 
*Adjusted for baseline outcomes and covariates (age, sex, race, BMI, KL score, hip OA, plasma 
biomarkers).  

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For Aim 1, the primary outcome will be self-reported pain, and plasma levels of OT as a modifier of a 
significant treatment (OT vs. P) response, using an intent-to-treat approach. Secondary outcomes 
include a standardized, multimodal experimental pain battery and physical, cognitive, and emotional 
functioning measures. For hypotheses H1a to H1e, we will use equation [1] to evaluate and test the 
effect of OT at 4-weeks post-intervention compared to P. Baseline outcomes and covariates (age, sex, 
race, hip OA, and inflammatory biomarkers) will be properly adjusted. A 50% reduction in self-reported 
pain intensity will demonstrate a clinically significant effect of OT compared to P. For Aim 2, the primary 
outcomes are proton MRS metabolites in frontal brain regions (tCr, MI, Cho) and plasma immune 
markers (IL-6, TNF-α, IL-10). For hypotheses H2a and H2b, we will use equation (1) to evaluate 
changes from baseline to post-intervention. Covariates (age, sex, race, hip OA) will be properly 
adjusted. For hypothesis H2c, we will use correlational tests and regression methods to evaluate the 
association between brain metabolites, systemic cytokines, and clinical pain to consider the inter-
individual variability in treatment response. Consistent with IMMPACT recommendations we will 
perform a secondary analysis considering total number and amount of rescue medication doses in a 
matrix alongside pain relief, with higher scores assigned to those patients with high levels of relief and 
minimum rescue, and lower scores assigned to patients who have rescued the most and have lower 
pain relief scores.77 For exploratory aim 3, similar strategies will be employed.  
 
7. Possible Discomforts and Risks 
 
Equipment used in this research meet all current safety standards, and all research staff will be highly 
trained in the use of all equipment. This study may include risks that are unknown at this time. Potential 
risks for this study are related to use of study product, neuroimaging, blood draw procedure, blood 
pressure measurement, the physical performance tests, the cognitive function tests, the sensory 
testing, and potential loss of confidentiality related to study participation, as discussed in detail below.  
 
All assessment will be conducted at the Clinical Translational Research Building, the Pain Clinical 
Research Unit (Dental Tower), the McKnight Brain Institute, and the Department of Psychology and all 
sessions will be conducted by trained and certified research staff, which will monitor potential adverse 
experiences and symptoms. We will do safety labs within 48 hours if participant withdraws due to 
potential adverse effects to study drug (feeling weak/tired/low energy or changes in mental status). 
During the testing sessions, a fully equipped defibrillator is available along with a semi-automated ECG 
cart. All personnel associated with the study have received CPR training and training on management 
of acute events including syncope, chest pain, acute dyspnea, focal neurological symptoms and 
abnormal vital signs. Portable defibrillators are available at the assessment site. Additionally, a study 
physician is available on call and contact numbers for emergency services are posted. Institutional and 
community EMS services will be activated if needed. If participants develop chest pain, shortness of 
breath, or dizziness at any point during a screening or assessment visit, they will be instructed to rest 
and to contact the center and their physicians if these symptoms persist or recur.  
 
Additionally, the study physician is available on call and contact numbers for emergency services are 
posted. Institutional and community EMS services will be activated if needed. If participants develop 
chest pain, shortness of breath, or dizziness at any point during a screening or assessment visit, they 
will be instructed to rest and to contact the center and their physicians if these symptoms persist or 
recur. 
 
Participants will be instructed to talk with the investigators about any discomforts that occur during the 
study. If for any reason the participant reports an injury, chest pain, leg swelling or pain, excessive 
shortness of breath, abnormal heart rhythm or dizziness, they will be referred to their doctor, or the PIs 

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will call the doctor or other health care provider.  
 
Prior to beginning data collection, all study coordinators undergo standardized training on all study 
procedures. A detailed checklist for each data collection element is in place to ensure all study 
coordinators are appropriately trained and able to conduct study procedures. Research coordinators 
will be certified in each element of the study visit including obtaining informed consent, administering 
questionnaires, protecting confidentiality of collected data, performing the test batteries. Any study 
coordinator who is found to not adhere to all aspects of the protocol will be required to complete 
additional training followed by re-certification.  
 
All research staff complete human subjects training required by The University of Florida institutional 
review board (IRB) and National Institutes of Health (NIH). This training includes education about the 
importance of maintaining confidentiality of personal health information. The study principal 
investigators or a co-investigator will be available to answer questions that arise during the informed 
consent process as needed. More information about specific protective measures against risk is 
outlined below. 
 
OT Nasal Spray Application  
We have been applying the identical drug compound in our current Oxytocin Aging Trial 
(IRB 201300801) over the last 3 years; we have currently completed over 100 older participants from 
a comparable age range and at the same dose and frequency and have no evidence of consistent or 
adverse reported side effects.  
Physiological Effects of OT. The physiological effects of OT include stimulating uterine contraction 
during the second and third stages of labor, facilitating the milk-ejection reflex in mammary glands of 
lactating (breastfeeding) women, contributing to aspects of the sexual response cycle (erection, 
ejaculation, and orgasm), and attenuating cytokine-mediated inflammation to promote wound healing 
(Uvnas-Moberg, 2003). OT, at high doses, can bind vasopressin receptors in the kidney reducing the 
excretion of urine and can stimulate sodium excretion from the kidneys (Gimpl, & Fahrenholz, 2001). 
OT can also indirectly inhibit release of adrenocorticotropic hormone and cortisol in response to stress 
(Bao et al., 2008). 
 
Safety of OT in Humans. The participant age group targeted in the present study is comparable with 
those tested in other studies, including a comprehensive meta-analysis that focused on potential risks 
and side effects associated with synthetic OT (given in the form of Syntocinon (Novartis), Pitocin, or 
our compound with the IND # 100,860; see MacDonald et al., 2011). This meta-analysis supports 
evidence that the use of synthetic OT nasal spray administered in the tested doses produces no 
consistent side effects or adverse events. In particular, MacDonald and colleagues collected data from 
n = 1,529 people treated with intranasal OT since 1990. In this review, participants did not report notable 
subjective side effects. Even though 18% of patients reported mild side effects, there was essentially a 
1:1 ratio of frequency among placebo and OT recipients. Additionally, the majority of participants (93%) 
were not able to discern drug effects from placebo. The reported side effects include increased 
calmness/euphoria, lightheadedness, drowsiness, headache, nasal irritation, and dry mouth/throat. In 
one of the few long-term studies, patients with constipation received intranasal OT (40 IU twice a day) 
for 13 weeks. Participants in this trial were queried about side effects weekly throughout the trial. Three 
female participants (2 OT, 1 placebo) reported severe vertigo on the first day of treatment (Ohlsson et 
al., 2002). Five participants in this trial reported menstrual disturbance, though four of them were on 
placebo. Additionally, in a recent clinical trial in older adults (mean age 80 years) by Barraza and 
colleagues (2013) OT (Pitocin) was administered over 10 days once a day at a dose of 40 IUs and no 

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significant adverse events were reported throughout the entirety of the study, indicating that OT can be 
safely used within this age group. 
 
There have been three reported cases of significant adverse reactions related to intranasal OT, all 
linked to OT’s potential to exert antidiuretic effects in high doses (by binding vasopressin receptors in 
the kidney; Joo et al., 2004). The first two of these reports involved the excessive use of intranasal OT 
and excessive IV hydration (Mayer-Hubner, 1996; Seifer et al., 1985), and the third was the result of 
long-term intranasal OT use (2.8-5.6 IU thrice-daily for 4 weeks; Ansseau et al., 1987). All three cases 
noted a decrease in the patients’ plasma sodium and osmolality levels. OT has a very small -- 0.25 % 
-- affinity for the renal AVP system (Liggins, 1963). Therefore, it can theoretically cause a syndrome 
similar to inappropriate ADH/AVP secretion -- SIADH, although carefully controlled human studies 
without water intoxication have not substantiated a natriuretic or antidiuretic effect in humans 
(Rasmussen et al., 2004). In none of Dr. Feifel’s studies were changes in sodium levels or osmolality 
noted, including those administering up to 168 IU of intranasal OT for 6 weeks. Additionally, 
cardiovascular effects have not been noted in intranasal human trials with non-pregnant patients, 
including longer-term trials of higher dose (den Boer & Westenberg, 1992; Epperson et al., 1996).  
The dose given in our research will be lower than in most other studies. For example, Epperson and 
colleagues (1996) gave five participants with OCD 160 IU of intransal OT daily for a week and another 
two patients 320 IU/day for a week and found no adverse effects with either dose including measures 
of blood pressure and osmolality. Dr. Feifel’s team has substantial experience with participants in a 
number of different studies receiving intranasal OT in various doses up to 168 IU (84 IU twice a day). 
They have administered 80 IU / day (40 IU twice a day) to patients with GAD for 3 weeks and found it 
was very well tolerated. In another small study looking at the effects of OT in individuals with 
schizophrenia, ten participants received 84 IU twice a day for 3 weeks. In another study eight 
schizophrenia participants received 6-weeks of 84 IU twice a day intranasal OT, while approximately 
24 participants so far have received 48 IU twice a day for 12 weeks. In none of these participants was 
there any evidence of either subjective side effects or objective evidence of physiological adverse 
effects (including blood work and measurement of urine osmolality).  
 
In the event of severe side effects while taking either OT or the P, the blind for that participant will be 
broken. In this case, we will have the participant contact his or her primary care physician. 
 
Excluded Medical Conditions. As a precaution, we will exclude participants who take vasoconstrictors 
such as vasopressin (e.g., desmopressin) or pseudoephedrine at time of study enrollment. Also, since 
OT can potentially produce antidiuretic effects (via activating vasopressin receptors on the kidney) we 
will exclude patients taking antidiuretic medication. As hypersensitivity to OT is a contraindication (other 
than certain cases of abnormal labor), we will exclude participants with a hypersensitivity to OT or 
vasopressin, given OT’s structural similarity to vasopressin.  
 
Drug-Interactions. Severe hypertension has been reported when OT is administered via IV during labor 
for 3-4 hours following prophylactic administration of a vasoconstrictor in conjunction with caudal block 
anesthesia. Cyclopropane anesthesia may modify OT's cardiovascular effects, producing unexpected 
results such as hypotension. There have not been any reports of drug-interactions with chronic 
intranasal OT administration in the many published studies in which patients took concomitant 
medications (Feifel et al., 2010; MacDonald et al., 2011; Pedersen et al., 2011). 
 
Laboratory tests. Participants will have blood drawn at screening and during the post-intervention visit 
to measure their blood chemistry and will provide urine samples for osmolality tests. Abnormal results 
will be brought to the principal investigator’s attention immediately. The results will be reviewed and 

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signed by the study clinician and Drs. Cruz-Almeida or Ebner. If a participant has both low sodium 
(<134mEq/L) and high osmolality (>1200L), we will conduct a second blood test. If the sodium is again 
low (<134mEq/L) in the repeat blood draw, the participant will be excluded. 
 
Assessment of Adverse Events. A standard operating procedure will be established which is followed 
to collect and deal with adverse events during the research project. In particular, adverse events will 
be systematically monitored both during the treatment phases, as well as 3 and 6 months following 
study completion. In particular, participants will respond to a side effect check list to detect any 
possible physiological reactions related to the drug administration. This will include series of open-
ended questions asked by trained research staff regarding any adverse events that have occurred 
since the last visit or phone contact. Aside from open questions about pain experienced in various 
parts of the body, dizziness or light headedness, research staff will inquire about changes in thirst or 
urination, as OT can alter water concentration in the kidneys in rare cases. Additionally, during the 3 
and 6 months follow up, participants will be asked to the WOMAC and PANAS questionnaires to 
assess pain and feelings. This report will be reviewed by the principal investigator and study physician 
in a timely fashion. Any serious untoward event, whether related or unrelated to the study drug or 
procedures, will be reported to the UF IRB and FDA immediately as per their regulations.  
 
Adverse events will be defined as any physical symptoms or side effects that began following 
administration of the study drug. All reported and observed adverse events will be tracked in a running 
adverse events participant log, which will contain information regarding dates, description, and 
severity. All adverse events will be coded using the most current version of the Medical Dictionary for 
Regulatory Activities (MedDRA). The number and percentage of participants reporting treatment-
emergent adverse events will be tabulated by treatment, system organ class and MedDRA-preferred 
term. Treatment-emergent adverse events will be those adverse events that begin or worsened 
following the first dose of study drug. Adverse events will be further classified by severity and 
investigator-assigned relationship to study drug. All reported and observed adverse events will be 
tracked on a running adverse events log (specific to each subject and maintained in his/her study file) 
and will contain information regarding onset/offset dates, time course (i.e., single, sporadic), severity, 
action taken regarding study drug, relationship to study drug, and whether it meets FDA criteria for 
“Serious.” Each reported event is reviewed by the principal investigator and the study physician in a 
timely fashion. Additionally, the principal investigator reviews all adverse events recorded in each 
participant’s log at the conclusion of study participation.   
 
In Case of Emergency. Participants will have 24-hour access to emergency care and will be provided 
with a means of contacting the on-call study doctor and research staff. Participants will be informed 
and encouraged to contact the study physician and study staff immediately with medical concerns or 
unusual reactions. Participants will also be informed of the closest Emergency Department location to 
their residence.  
 
Data and Safety Monitoring Plan. A Data Safety Monitoring Plan will be in place. In particular, the 
following procedures will be implemented to ensure data and participant safety. Study progress and 
safety will be reviewed by the principal investigators in collaboration with Dr. Roland Staud, M.D., the 
study MD, and Dr. Feifel, M.D., Ph.D., the sponsor of the IND and consultant on the project.  
 
We will stop the intervention if 30% or more of the participants in the OT condition report 10 or more 
(out of forty-four) of the side effects at moderate to severe levels over more than 2 weeks as acquired 
during the weekly check in phone calls during the intervention phase. Data collected prior to stop of 

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intervention will be used for analysis. All participants who went through the intervention phase of the 
study will be followed up by phone calls at multiple time points to ensure safety; every 7 days during 
the intervention, 7 days post intervention, 3 months post intervention, and 6 months post intervention. 
Progress reports, including participant recruitment, retention/attrition, and adverse events will be 
provided to an Independent Safety Monitor(s) for reviews on a bi-annual basis. The Independent Safety 
Monitor(s) for this study will consist of an established senior investigator not associated with our study. 
A study end report will be compiled and will include a list and summary of adverse events. In addition, 
this report will address: (1) whether adverse event rates are consistent with pre-study assumptions; (2) 
reason for dropouts from the study; (3) whether all participants met entry criteria; (4) whether 
continuation of the study is justified on the basis that additional data are needed to accomplish the 
stated aims of the study; and (5) conditions whereby the study might be terminated prematurely. The 
annual report will be signed by the Independent Safety Monitor and will be forwarded to the IRB, NIH, 
and FDA. The Independent Data Safety Monitoring Plan will also require that all significant serious 
adverse events that may be possibly related to the study participation will be reported to the IRB, FDA, 
and NIH within 48 hours of the principal investigators learning of the event. In addition, any 
unanticipated serious adverse events that may increase the risk of the research for participants or 
potential participants will be reported to the IRB and the NIH within 48 hours of the principal 
investigators being informed about the event. This study will be stopped prior to its completion if: (1) 
the intervention is associated with adverse effects that significantly impact the risk-benefit ratio, (2) 
study recruitment or retention becomes futile, (3) any new information becomes available during the 
trial that necessitates stopping the trial; or (4) if independent safety monitor indicates that stopping the 
trial is necessary due to adverse event frequency or severity. 
 
ClinicalTrials.gov Requirements. In accordance with Public Law 110-85 and NIH guidelines, the 
proposed research will be registered with ClinicalTrials.gov prior to commencement of study 
procedures involving participants. 
 
Magnetic Resonance Imaging (MRI)/ Magnetic Resonance Spectroscopy (MRS) 
MRI and MRS are used routinely for medical care and are very safe for most people, but participants will 
be monitored during the entire scan in case any problems occur. The risks of MRI/MRS are: 
• The scanner contains a very strong magnet. Participants may not be able to have the MRI/MRS if 
they have any type of metal implanted in their body, for example, any pacing device (such as a heart 
pacer), any metal in their eyes, or certain types of heart valves or brain aneurysm clips. Therefore, 
participants will be extensively screened. Participants who would normally be excluded from getting 
an MRI/MRS for safety reasons will be excluded, applying criteria for exclusion that are more 
stringent than those imposed for standard clinical MRI/MRS scans.  
• There is not much room inside the scanner. Participants may be uncomfortable if they do not like to 
be in close spaces ("claustrophobia"). Participants will be screened for known claustrophobia.  
• The scanner produces a loud hammering noise, which has produced hearing loss in a very small 
number of people. Participants will be given earplugs to reduce this risk. In addition, they will be 
informed of this possibility in the consent form and that they may immediately withdraw from the 
study at any time. During the procedure, participants will be able to talk with the staff through a 
speaker system, and, in the event of an emergency, participants can tell them to stop the scan.   
 
During neuroimaging, participants will be situated comfortably on the scanner table, with a head 
mounted, MRI compatible eye tracker system attached. Visual stimuli will be presented using an LCD 
screen inside the scanner. Brain image acquisition will take place on a 3T Siemens Prisma human 
imaging system at AMRIS, at the McKnight Brain Institute, employing pulse sequences and hardware 

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that have been approved by the FDA for human clinical use. All MRI/MRS safety guidelines and 
precautionary steps established by the AMRIS will be strictly followed. At the end of the session, a post-
scan debriefing questionnaire will be administered that examines discomfort during and after the 
scanning. 
 
Blood Draw 
The risks of drawing blood from a vein include discomfort at the site of puncture; possible bruising and 
swelling around the puncture site; rarely an infection; and, uncommonly, faintness from the procedure. 
 
Blood Pressure Measurement 
The risks of placing a blood pressure cuff on a participant’s arms are that it may cause pinching or slight 
bruising.   
 
 
Physical Tests 
There is a risk of losing balance and falling or development of chest discomfort due to coronary 
ischemia or dyspnea due to heart failure or lung disease associated with the physical performance-
based testing (e.g., the ¼ mile walk test, balance tests, rising from a chair). We will minimize this risk 
by: (1) safely escorting participants to chairs located along the walking course should they become 
unsteady; (2) following participants at a close distance; and, (3) being at participants’ side should they 
need assistance. Research staff members will be trained in the conduct of the physical performance 
tests before they work with study participants. Study staff members are trained not to perform these 
tests if they feel that testing is unsafe. In addition, participants will be asked whether they feel the test 
is safe. Those who state it may be unsafe will not be allowed to complete the test. Staff members will 
be trained to protect against falling and will be trained in CPR. They will be trained in activating the 
emergency response system at the research facility.   
 
Sensory Testing 
The sensory testing procedures may be uncomfortable or unpleasant, in that participants may 
experience 
some 
temporary 
discomfort 
from 
the 
thermal, 
pressure, 
and 
mechanical 
stimulation. However, if the participants feel the sensation is greater than they wish to tolerate, they 
can stop any of the procedures at any time. 
 
Personal Information 
Some of the questions participants will be asked may be personal in nature and may make participants 
feel uncomfortable. Time will be made to talk with the participant if they appear to be distressed. We will 
be asking for information about sensitive issues, such as mood and thoughts of suicide which may make 
participants feel uncomfortable. If they are uncomfortable answering these questions, they can choose 
not to answer and discontinue participation in the study. Some people, when asked such questions, 
experience strong emotional reactions that may require counseling. If they do, they are strongly 
encouraged to tell the Principal Investigator, who can make an appropriate referral to the Psychology 
Clinic or to the UF Counseling & Wellness Center at (352) 392-1575. If we find that the participant is 
suicidal, he/she will be excluded from further participation in the study and an appropriate referral will be 
made. If we should discover, based on the questionnaires or formal clinical interview, that the participant 
experiences marked depression or suffer from another psychiatric condition, we will offer to make an 
appropriate medical, psychiatric, and/or psychological referral. 
  

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Confidentiality 
Data that will be collected from human subjects for this project will include behavioral performance 
measures, rating scales assessed through interviews and patients’ responses to self-rated scales, 
physiological, and neuroimaging data. Data will be collected specifically for the proposed research 
project. Access to individually identifiable private information about human subjects will be limited to 
research staff affiliated with the project. Research records will be kept confidential to the extent provided 
by law. The collection and submission of medical information will be accomplished with strict adherence 
to professional standards of confidentiality. Participants’ medical information will be kept in a secure 
location accessible only to research staff associated with this study. Participants will only be identifiable 
by ID number, and any published findings resulting from the study will not refer to or identify individuals. 
A number of methods will be employed to maintain confidentiality of participants. First, data will be 
collected in secure spaces where the session cannot be overheard. Secondly, only study investigators 
and key research staff (i.e. data manager and study programmers) will have access to the study 
database. Third, participants will be assigned a unique study identifier. Individual names are not linked 
with collected data in the password-protected study database and only the unique study identifier will 
be used. A file linking the participant name and contact information and their specific study identifier 
will be kept separately and will be password protected and only accessible to study team members. 
Fourth, collected data will be maintained in locked computer files and file cabinets to which only study 
team members have access. Collected data will be used only for research purposes. Published data 
will not contain any individual identifiers. Finally, all research staff members have to retake refresher 
course certification exams every year. 
 
Informed Consent 
Prior to entry in the trial, the investigator(s) or study coordinator(s) will explain to potential participants 
the aims, methods, reasonably anticipated benefits, and potential hazards of the trial and any 
discomfort it may entail. Subjects will be informed that their participation in the study is entirely 
voluntary and that they may withdraw consent to participate at any time. They will be told that 
competent physicians/lab personnel will examine their records but that personal information will be 
treated as strictly confidential and will not be publicly available. Subjects will be given the opportunity 
to ask questions and will be given sufficient time to review all of the relevant information associated 
with the study. After this explanation and before entry to the trial, the subject’s consent will be obtained 
and documented via signature of an informed consent form by both the subject and the person 
conducting the informed consent discussion. If signed informed consent cannot be obtained, the 
subject will not be included in the trial.  
 
Inclusion of Women and Minorities/ Inclusion of Children 
Men and women will be approximately equally represented in the sample. No clear evidence exists yet 
that OT levels vary between cultures. However, prosocial behavior associated with the OT system, 
have been shown to vary by culture (Kim et al., 2010). In addition, there is evidence that OT-related 
polymorphisms may vary across culture (Liu et al., 2010). Based on these empirically supported 
considerations we will enter race/ethnicity as covariate into our statistical models.  
 
The proposed research will address effects of OT on pain, cognition, inflammation, and physical 
health in older men and women. Children are not the focus of this project, and by design, children will 
not be included in the study. 
 
8. Possible Benefits 
 

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There are no direct benefits for study participation. There may be benefits that we are not yet aware of. 
The report about the results of the study will be made available to study participants as well as others in 
the community. However, the greatest benefit will be to society as a whole. Scientific knowledge 
advances slowly, but study results will increase our understanding of pain and cognition in aging. Such 
knowledge may be implemented in intervention programs that may have the potential to increase function 
and personal well-being.  
 
9. Conflict of Interest 
 
There are no conflicts of interest with this project.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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PANDA Ancillary Project Protocol 
 
 
 

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Protocol  
  
1. Project Title  
  
Pain and Nutrition in Dementia and Alzheimer’s (PANDA); ancillary to the UCOPE Study: 
Understanding Cognition, Oxytocin, and Pain in Elders)  
  
2. Investigator(s)  
  
Dr. Larissa Strath (PI)  
Dr. Yenisel Cruz-Almeida (co-I)  
  
3. Abstract  
Growing evidence suggests the presence of dysregulated pain modulation in older adults, and affect 
which may heighten age-associated risk for chronic pain. Additionally, chronic pain and Alzheimer’s 
Disease and related dementias (AD/ADRD) are highly prevalent and comorbid in older adults, and 
research suggests that they may have overlapping etiologies and pathologies. Chronic pain may a 
predictor for the development of AD, and almost half of AD patients report having pain. Thus, 
understanding of the shared mechanisms underlying both is critical in order to develop effective 
treatment and prevention modalities. Recently, epigenetics has been implicated in both disease states, 
with many modifications of the epigenome that may go on to result in immune system dysfunction, of 
which is a hallmark of both chronic pain and AD. While there are many environmental factors that can 
influence the epigenome, nutrition status has been shown to be one of the most common and modifiable 
factors therein. Thus, it may be efficacious to understand dietary interactions with the epigenome to 
target epigenetic regulation of the development and maintenance of chronic pain and AD. Therefore, 
the overall goal for this mentored career development proposal is to fill this knowledge gap and 
determine the influence of overall diet pattern as well as Vitamins A and D specifically on the epigenetic 
environment as it relates to chronic pain and AD/ADRD. This study will assess dietary differences and 
their associations with differences in epigenetic aging, pain, and cognition in individuals with and 
without chronic pain. This proposed career development plan extends from the PIs prior work in dietary 
and immune system modulation of pain, and will forge a path towards understanding and investigating 
side-effect free nutrigenomic targets that improve pain and AD/ADRD outcomes in older adults.  
  
4. Background  
Chronic pain is 
highly prevalent starting in middle age. Globally, approximately 1.5 billion people experience chronic pain, 
and in the United States (US) alone, 1 in 3 individuals will have chronic pain at any given time1. It has significant 
negative physical, psychosocial, and economic costs1-3. In the US, chronic pain represents a major public health 
issue, as it is the most common reason for seeking medical care, increases physical and cognitive disability, 
increases risk of opioid abuse4. Since chronic pain is more prevalent in older adults (Figure 1) and the number 
of adults over the age of 65 is expected to increase from 40 to 88 million by 2050 5, the health concerns related 
to chronic pain for both older individuals and society at large will significantly increase in the coming decades. 
Like chronic pain, the number of individuals living with Alzheimer’s Disease (AD) and Alzheimer’s Disease 

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Related Dementias (ADRD) in the US is expected to almost triple to 14 million in the next 30-40 years4. Dementia 
and AD symptoms vary at the early stages of the disease, increase in prevalence and severity as the disease 
progresses, and include cognitive, behavioral, psychological, and physical (i.e., falling, jumbled speech, inability 
to coordinate movement) symptoms6.  Health concerns related to AD/ADRDs will also significantly increase in 
the near future, especially if research distinguishing the etiologies, as well as successful interventions/prevention 
strategies are not of upmost importance.  
Chronic pain and AD/ADRD are both 
characterized by neuroinflammatory processes that are controlled by the epigenome. Throughout the 
literature, a bidirectional association is present between chronic pain and AD, though a clear mechanistic link 
remains to be elucidated. Approximately 48.5% of AD patients report having chronic pain, and pain intensity is 
also positively correlated with dementia severity7.  During the preclinical phase of AD and related dementias, 
there is a 20 to 30-year span where cognitive deficits are not present, but pathological changes may already be 
occurring 8, 9. It is during this age range prior to AD diagnosis that we see the peak prevalence of multiple chronic 
pain conditions. Recent reports suggest that chronic widespread pain predicts cognitive decline, as chronic pain 
was associated with a 43% increase in all-cause dementia, and a 47% increase in AD/ADRD risk10.  Both disease 
states are characterized by activated microglia11 and central nervous system (CNS) neuroinflammation. The 
relationship of chronic pain and neuroinflammation is well established, with the presence of activated microglia 
being a hallmark of chronic pain conditions12. Recently, inflammation-associated PET-MRI studies have shown 
microglial activation in the brains of AD patients. Microglial activation has been found to be present before 
cognitive decline in AD patients, suggesting its early participation in AD pathology13. There is evidence to suggest 
that such immune dysfunction seen in both chronic pain and AD is regulated by the epigenome, which may serve 
as a reasonable target of intervention in order to control the progression of both disease states12, 14.  Epigenetic 
modifiers, such as DNA methylation, histone modification, and microRNA expression, are important modulators 
of gene expression.  These modifiers, influenced by external environmental factors, are what aid and abet 
microglia to transform themselves into their various phenotypes in neurodegenerative disease14 and have been 
found to be differentially methylated in both patients with chronic pain and patients with AD15, 16. Epigenetic 
modifications that lead to immune system dysfunction may be a key player in the similar etiologies and 
pathologies seen in both chronic pain and AD/ADRD.  Because of the epigenome’s readiness to respond to 
changes in its environment, interventions targeting it may help to prevent and treat subsequent AD/ADRD and 
chronic pain.  
Studies examining the relationship between chronic pain and AD/ADRD have lacked rigor and not taken 
into account pain impact, likely leading to mixed results. Historically, studies exploring the relationship 
between pain and AD/ADRD have simply used a binary pain/no pain variable potentially leading to studies 
showing significant relationships between pain and cognitive outcomes and those showing no significant 
differences17-33.  However, recent evidence from the pain field suggests that experiments must also take pain 
impact into account, not just its prevalence34.  Pain impact not only serves as a proxy for pain intensity and 
severity, but also takes into account the amount of interference in daily-life tasks the pain causes.  Typically, 
chronic pain measures are used to derive at least three impact groups: pain-free controls, low-impact pain, 
meaning there is pain present but it does not significantly modify daily living; and high-impact pain, or pain that 
significantly disrupts daily life-related tasks. We (Strath et al., in process; Peterson & Strath et al, under review) 
and others 34 have suggested that individuals experiencing high-impact pain show the greatest declines across 
a variety of health related outcomes, including cognition.  Thus, it is imperative to stratify chronic pain groups if 
we are to truly understand the relationship between pain and cognitive diseases such as AD/ADRD.   

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Diet pattern and nutrition status have been previously implicated 
in chronic immune system activation and inflammation and epigenetic regulation. The relationship 
between inflammation and diet is well-documented, and many elements of diet have been reported to activate 
immune cells and trigger an inflammatory response35 36.  Excess amounts of dietary oils and fatty acids have 
been shown to participate in lipid oxidation, leading to reactive oxygen species (ROS) and subsequent 
inflammation37. Omega-6 polyunsaturated fatty acids (PUFAs), such as linoleic and arachidonic acid, are 
precursors for inflammatory prostaglandins38, and are consumed in much higher amounts in the typical American 
diet than anti-inflammatory omega-3 fatty acids39. Excess carbohydrates increase the presence of Advanced 
Glycation End Products (AGEs) that bind to immune cells and stimulate a pro-inflammatory response40. In 
addition to pro-inflammatory effects, a diet can have anti-inflammatory effects as well. A Mediterranean diet can 
reduce markers of inflammation in obese individuals 41 and in patients with osteoarthritis 42 and rheumatoid 
arthritis43 44. Interestingly, one study found that the patients on a Mediterranean diet showed significant reductions 
in inflammatory markers prior to weight loss, suggesting that the diet itself produced anti-inflammatory 
effects45.  Studies have shown that specific micronutrients, such as Vitamins A and D, may have the ability to 
control gene expression by interacting with the epigenome.  Both Vitamins A and D have their own receptors 
(Vitamin D Receptor or VDR, and the Retinoid X Receptor or RXR) are expressed both on cells as well as DNA46, 
47 (Figure 3).  These receptors can act as transcription factors participating in DNA transcription or physically 
block transcription from occurring, depending on the scenario.  Additionally, there is also evidence to support 
that both vitamins and their receptors may participate in DNA methylation mechanisms, furthering their potential 
ability to influence the epigenome and downstream protein expression48, many genes of which function to 
regulate the immune system and inflammation49-52.  Evidence suggests that not only are many chronic pain and/or 
AD patients deficient in these vitamins, but have differential DNA methylation status on these 
immune/inflammation-related genes influenced by Vitamins A and D (Strath et al, 2022, in process)53-55; and the 
subsequent differentially expressed genes may contribute to pain and cognitive decline56.  Additionally, there is 
evidence that Vitamin A deficiency may be associated with dysfunctional microglia57. Vitamin D deficiency is a 
risk factor for the development of AD and chronic pain, and low levels of this vitamin are related to increased 
cognitive decline58, 59. Vitamin D has also been shown to mitigate neuroinflammation present in the brain60. Both 
basic science and clinical models also show that diets low in these micronutrients are linked to increased pain 
severity and disability in chronic pain, as well as increased Aβ and tau proteins in serum and PET scans, as well 
as more severe cognitive deficits in AD 58. In addition to being more cost-effective than most pharmaceutical 
interventions, nutrition based-interventions carry an incredibly positive side-effect profile. Finally, nutrition 
interventions are highly adaptable, and can be adjusted to accommodate cost, flavor profiles, as well as be 
inclusive to cultural and religious practices, making them it a suitable strategy for all regardless of background.  
Rigor of the prior research. There are noted gaps and weaknesses of the prior research that need to be 
addressed in order to move this field forward that this application plans to address.  Historically, the consideration 
of pain impact has been overlooked, likely leading to inconsistent results among the literature observing the 

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relationship between AD/ADRD and chronic pain. Additionally, studies implicating lifestyle factors such as 
nutrition as a possible mechanism influencing the relationship between pain and cognitive disease have not been 
completed, despite evidence of nutrition status influencing on both disease states independently. Finally, the 
examination of epigenetics (influenced by nutrition) such as DNA methylation and epigenetic/cellular aging as a 
common mechanism driving both pain and AD/ADRD in tandem has not been appreciated. This proposal not 
only will provide the candidate with the opportunity to train in an outstanding research environment, but also 
allow her to contribute to filling the gaps in the literature that will allow the field to progress towards solutions to 
solve the complex problems seen in chronic pain and AD/ADRD.  
5. Specific Aims  
Specific Aim 1: Determine the association among DII, epigenetic clocks/cellular aging and cognitive 
function middle-age and older adults with low-impact pain, high-impact pain and pain free controls.  
Hypotheses 1a-d: Individuals with chronic pain will (H1a) have a more positive/inflammatory DII, which will be 
associated with (H1b) accelerated epigenetic aging and (H1c) greater cognitive impairment.  These associations 
will be more significant in the high-impact pain group compared to those with (H1d) low-impact pain and pain-
free controls.  
  
6. Research Plan  
We propose a cross-sectional, observational study design that will assess the relationship between 
pain, cognition and dietary pattern in older adults with and without symptomatic knee OA pain.  This 
will be completed in 2 experimental sessions approximately one week apart.  After initial screening, 
eligible participants will undergo the sessions (health and sensory sessions) for collection of clinical, 
functional (physical, cognitive, emotional), QST, and blood-based biomarker data lasting 2-3 hours.   
Participants: This study will be ancillary to one of primary mentor Dr. Cruz-Almeida’s ongoing 
studies,  significantly increasing feasibility. Thus, participant data for this phase will be collected from 
previously obtained experimental pain outcomes (QST), cognitive outcomes, self-reported 
demographic variables (age, sex/gender, race/ethnicity, education, household income), other covariate 
(depression, anxiety, smoking, body mass index) information due to their known influence on pain 
outcomes, as well as previously collected and stored blood samples (n=50).  Additionally, we plan on 
enrolling 40 more participants into the PANDA study that do not meet the inclusion/exclusion criteria 
of the parent UCOPE study. Based on power-analytic considerations, we plan to obtain data for a total 
of 90 individuals of both sexes (approx. 50% male) from various ethnicities. This sample size includes 
a 20% attrition rate. Older adults over 55 years of age who meet American College of Rheumatology 
clinical criteria for knee OA78 of at least six months duration, experience pain on more days than not, 
with moderate pain at baseline (i.e., > 3/6 in the VDS), and who have elevated levels of plasma IL-6 
(>2.5 pg/ml) will be considered for participation. Both community-based and clinic-based recruitment 
methods established in our labs will be utilized. We will also utilize IRB approved registries to contact 
potential participants.   
Exclusion criteria will align with study and safety requirements related to 1) Pain testing: participants 
will be excluded if they have concurrent medical or arthritic conditions that could confound symptomatic 
knee OA-related outcomes or coexisting disease that could preclude successful completion of the 
protocol including: systemic rheumatic condition (e.g. rheumatoid arthritis, systemic lupus 
erythematosus, fibromyalgia); a history of clinically significant surgery to the index knee; uncontrolled 
hypertension (>150/95); poorly controlled diabetes (HbA1c>7%);; cardiovascular or peripheral arterial 
disease; serious psychiatric disorder requiring hospitalization within the past twelve months or 
characterized by active suicidal ideation; diminished cognitive function that would interfere with 
completion of study procedures (i.e., MoCA score < 25)];81 and 2) pregnant individuals will be 
excluded; and 3) enrolled in another interventional research study.   
Initial screening: After phone consent, all potential participants will undergo an initial screening 
interview, via telephone or in-person depending on the recruitment setting (Figure 7). This screening 

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procedure will include a knee OA screening interview that has shown 87% specificity and 92% 
sensitivity for detecting knee OA.82 This interview includes four questions regarding knee pain and 
swelling and previous diagnosis of knee OA. The initial screening will also assess MRI eligibility, age, 
gender, handedness, and additional health history information, and demographic information such as 
education level, household size and race/ethnicity for sample descriptive purposes. The Telephone 
Interview for Cognitive Status (TICS) will be given to participants to assess cognitive status. Eligible 
individuals will be scheduled for the Health Assessment Session.   
Health Assessment   
Urine and blood samples. After written informed consent, participants will provide a urine sample to 
determine osmolality and a fasting blood sample to evaluate standard clinical parameters 
(Comprehensive Metabolic Panel (CMP-14) Blood Test), which will be reviewed by Co-I Staud to 
determine study continuation. Following established pilot study procedures, blood samples will also be 
used for determination of plasma neuropeptide (e.g., OT, arginine vasopressin (AVP)) concentrations 
and inflammatory markers (e.g., IL-6, TNF-α, C-reactive protein (CRP)); as well as genetic markers 
associated with OT. This session will take place in the mornings to accommodate for fasting and to 
control for circadian fluctuations. For women under the age of 62, pregnancy tests will be conducted at 
study start. Samples may be collected during any session that is most convenient for the participants 
as long as this is collected before randomization.   
Dietary Inflammatory Index.  The Dietary Inflammatory Index (DII) was developed to provide a 
quantitative means for assessing the role of diet in relation to health outcomes ranging from blood 
concentrations of inflammatory cytokines to chronic diseases. For the K99 phase, diet data has been 
previously collected in the form of a 24-hour food recall.  To collect diet data, participants were asked 
to document food and beverages consumed, as well as supplements taken 24 hours prior to their 
visit.  Assessments were conducted interview-style by a trained research assistant in order to probe 
deeper into the details of meals.  Visual aids such as standard measuring cups, plates, and drink cups 
in various sizes etc.  were provided to aid in accuracy. These data will then be entered into the Nutrition 
Data System for Research (NDSR) for nutrient analysis. Following quantification, nutrient values  will 
be used to calculate DII score according to the instructions laid out by Hebert & Shivappa et al65.  
Vitamin A and D Analyses. In order to quantify serum Vitamin D levels, the Quantikine® Human 
Vitamin D BP immunoassay (R&D Systems) will be employed. To quantify Vitamin A levels, a 
Colormetric Human Vitamin A ELISA Kit (Novus Biologicals) will be used. Kit-specific protocols will be 
used during quantification.   
Epigenetic Analyses. Details regarding the protocol for processing and analyzing epigenetic data 
published elsewhere 66, 67.  In short, the raw data generated by Illumina EPIC array (.idat files) will 
undergo quality control and normalization prior to the calculation of DNAmGrimAge via an online 
calculator (dnamage.genetics.ucla.edu). The age-adjusted AgeAccelGrim variable will be calculated as the 
difference between chronological age and DNAmGrimAge and used throughout the analyses.   
Physical examination. Height and weight will be measured and Body Mass Index (BMI) will be 
calculated as it is significantly related to pain symptoms in OA.83 Participants will complete a thorough 
Pain and Medical History Questionnaire, including a review of bodily systems assessing the reported 
duration of OA, current and past treatments for OA, comorbid conditions, and current medication use 
as in our previous knee OA studies.5,57 Information regarding hormone replacement therapy will be 
obtained for both sexes, and for women, information regarding menopausal status, as this may interact 
with baseline OT levels and OT intervention effects.84 If there are concerns with eligibility, participants 
will undergo a Physical Examination by the study rheumatologist (Co-I Staud) to: 1) confirm the 
diagnosis of knee OA according to ACR clinical and radiographic criteria;78 2) rule out any exclusion 
criteria; and 3) identify the most symptomatic knee. Manual examination of joint tenderness may be 

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performed bilaterally for hands, hips, and knees. Symptomatic hip OA is common in the knee OA 
population85-87 and is associated with disability87 and thus will be included as a covariate.   
Clinical pain will be assessed according to location, overall pain severity, and pain interference with 
daily activities. These measurements will encompass the key dimensions for pain assessment as 
recommended by the American Geriatrics Society88 and according to the pain taxonomy by the 
Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and 
Networks and the American Pain Society group (AAPT).89,90 A Verbal Descriptor Scale (VDS) will assess 
changes in pain intensity before and after treatment. The VDS has anchors of “No pain” (scored as 0) 
and “The most intense pain imaginable” (scored as 6) and is easier to understand and preferred over 
numerical rating scales by older individuals,67 and has been effectively utilized in our pilot study. We will 
also administer the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC),91 a 
reliable, well-validated measure of lower extremity pain and function in individuals with knee OA. 
Summary scores of the WOMAC range from 0 (No pain or disability) to 96 (Extreme pain or disability).   
Knee x-ray. Weight-bearing radiographs will be taken for all participants. Co-I Staud will determine the 
Kellgren-Lawrence (KL) score and indicate which compartment(s) are affected in each knee (medial, 
lateral, patellofemoral) to determine study continuation. KL scores will be assessed in a blinded manner. 
This is only done at the baseline visit.   
Sensory Assessment Visit  
Pain and psychosocial questionnaires. Multiple psychosocial factors have been related to chronic 
pain. We will assess psychosocial factors across the following broad domains. 1) Pain coping: The 
Coping Strategies Questionnaire-Revised (CSQ-R)94 consists of 27 items relating to how individuals 
cope with pain. It comprises six subscales based on pain coping strategies that individuals report (i.e., 
diverting attention, catastrophizing, praying and hoping, ignoring pain sensations, reinterpreting pain 
sensations, and coping self-statements). 2) Affective distress: The Beck Depression Inventory, 2nd 
Edition95 is a widely used depression scale that assesses affective (e.g., sadness, loss of interest), 
cognitive (e.g., worthlessness, guilty feelings), and somatic (e.g., changes in sleep, tiredness or fatigue) 
symptoms common amongst depressed individuals. It contains 21 self-report items assessing the 
frequency and severity of depressive symptoms over the previous two weeks.   

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Since item # 9 from the Beck Depression Inventory 
refers to suicidality, the experimenter will, before the end of the test session, review the participant's 
response to this item, and if the participant has chosen response option 2 = “I would like to kill myself 
“or 3 = “I would kill myself if I had the chance”, the experimenter will contact the PIs immediately and 
the PIs or their designee will contact Dr. Dawn Bowers (or her designee) at the University of Florida 
Psychology Clinic (352-265-0294) who will make recommendations. In the unexpected event that the 
clinic personnel are not available, the Alachua County Crisis Center will be contacted. The same 
procedure will be implemented for the post-intervention assessment. The Positive and Negative 
Affect Scale (PANAS) is a 20-item scale that assesses positive and negative affect.96 The PANAS 
has demonstrated adequate reliability and validity.97 For this study, participants will be requested to 
provide “state” information by responding to items “at the present moment.” 3) Satisfaction/quality 
of life: We will assess self-reported quality of life using the 36-Item SF Survey Quality of Life98 
consistent with our pilot study, while the Satisfaction with Life Scale (SWLS)99 will assess satisfaction 
with people's lives as a whole. 4) Sleep: Self-reported sleep quality during the past month will be 
measured using the Pittsburgh Sleep Quality Index (PSQI).100 5) Interoceptive awareness: We will 
assess self-reported interoceptive awareness using the multidimensional assessment of interoceptive 
awareness (MAIA)114 6) Chronic Stress: Using the Daily Stress Inventory, we will collect 
participants’ self-reported daily assessment of the sources and individualized impact of relatively 
minor stressful events.11520 7) Perceived Stress Scale: Participants fill out a self-report assessment of 
their thoughts and feelings during the last month.116 8) Impulsivity: We will assess self-reported 
behavioral inhibition using the Behavioral Inhibition System and Behavioral Activation System 
(BIS/BAS) scales.117 9) Neuropathy: Individuals will respond to the PainDetect questionnaire to 
assess neuropathic pain detection. If an individual scores greater than 12, their clinical pain for each 
area of testing will be assess during the quantitative sensory testing session.118 10) Empathy: We will 
assess empathy using the Affective and Cognitive Measure of Empathy (ACME) questionnaire.119 11) 

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Back Pain: If an individual indicates they experience back pain, we will assess such pain using the 
Chronic Low-Back Pain (Minimal Dataset)120, Oswestry Low Back Pain Disability Questionnaire121, and 
Brief Pain Inventory122 questionnaires.   
Quantitative Sensory Testing (QST). Participants will undergo QST to determine responses to 
mechanical and thermal stimuli and conditioned pain modulation (CPM) (Figure 9; see also5,12,101). We 
will randomize the order of thermal and mechanical testing. Cold pressor assessment, including 
conditioned pain modulation, will always occur last to avoid carryover effects. Patients’ medications 
and current clinical pain will also be confirmed.   
Mechanical testing procedures. Pressure pain threshold (PPT) will be assessed at the medial and 
lateral joint lines of the index knee, and at the ipsilateral quadriceps and trapezius muscles. For all PPT 
measurements, after an initial practice trial, three trials will be conducted and their average will be 
computed for data analysis. Using a digital, handheld, clinical grade pressure algometer (Algomed, 
Medoc, Ramat Yishai, Israel), the examiner will apply a constant rate (30 kPa/second) of pressure and 
the participant will press a button when the sensation first becomes painful, at which time the device 
records the pressure. Punctate Mechanical Pain will be assessed at the patella of the index knee and 
the dorsal aspect of the ipsilateral hand using a nylon monofilament (Touchtest Sensory Evaluator 6.65) 
calibrated to bend at 300g of pressure. As in our previous studies,5,12,57 participants will provide a pain 
rating following a single contact, after which they will provide another pain rating following a series of 
ten contacts at a rate of one contact per second. The difference between the pain rating for the single 
versus multiple contacts reflects temporal summation of mechanical pain.  
Thermal testing procedures. Thermal stimuli will be delivered to the (most) affected knee and/or to 
the ipsilateral forearm and/or thenar eminence, in randomized order, using a Medoc Pathway Thermal 
Sensory Analyzer (Ramat Yishai, Israel). Heat pain threshold will be assessed at each site, followed 
by heat pain tolerance and temporal summation. Heat pain thresholds and tolerances will be assessed 
using an ascending method of limits as in previous studies.5,12,57 Temporal summation of thermal pain 
will be assessed using the same stimulus parameters as previously reported by us and others.5,12,57 To 
measure Cold Pressor Pain, a modified cold-pressor procedure will be conducted. Each participant will 
complete a series of 60-second immersions in cold water baths at 8ºC, with water temperature 
maintained (+0.1ºC) by a refrigeration unit. Participants will immerse their left hand up to the wrist with 
their fingers spread apart. Participants will report when they first feel pain, and this time point will be 
recorded as the pain threshold. Then, they will continue for one minute or until they report intolerable 
pain. If a participant terminates early, the time at which they terminate will be recorded as pain 
tolerance. Participants will be prompted to rate the intensity of the cold-pressor pain at 30-sec 
intervals.   
Conditioned Pain Modulation (CPM) will be used to assess pain-inhibitory function. The conditioning 
stimulus will be the cold pressor task applied to the left hand, which will be tailored for each participant 
to achieve a stimulus that produces moderate pain (i.e., a rating of 40-60 on the 0-100 scale) and can 
be tolerated for a 60-second period. The test stimulus will be heat pain applied to the opposite ventral 
forearm, at a stimulus intensity which produces moderate but tolerable pain. First, baseline heat pain 
responses will be assessed, after which the participant will immerse their hand in the cold water bath 
for 60 seconds. Immediately afterwards the heat pain will again be applied to the opposite arm and pain 
ratings will be obtained.   
Short Physical Performance Battery (SPPB) and Mobility Assessment. As a performance-based 
indicator of OT’s effect on function we will use this brief assessment consisting of four lower-extremity 
function measures: standing, balance, walking speed, and ability to rise from a chair. These measures 
have been standardized and are widely used in older populations and have been used in our own 
labs.102,103 We will also measure movement-evoked pain during each task which is associated with 
central pain processing in knee OA.103 Participants will also be asked to undergo a number of mobility 

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Protocol:  IRB201801467 (UCOPE Study) 
 
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assessments. Participants will be asked to walk over a mat without any obstacles, as well as stepping 
over an obstacle, and while performing a cognitive task. Some tests will be performed while walking 
over an instrumented walkway, which measures spatiotemporal gait parameters.  
Hypotheses and data-analytic strategy: Prior to the testing of proposed hypotheses, each variable 
will be carefully examined to identify missing values, statistical outliers, and violations of relevant 
assumptions (i.e., Durbin-Watson, Shapiro-Wilk). Sensitivity analyses would then be completed to 
examine differences in results between variables with missing data and those same variables with data 
imputation.  A corrected threshold will be set to 0.05, two-tailed. Descriptive statistics will be computed 
and represented as percentages or means (standard deviations). Group differences (pain impact 
groups; Vitamin A and D clinical cutoff differences) among potential covariates of interest will be 
examined using a series of one-way analysis of variance tests (ANOVAs) with follow-up/post hoc 
Bonferroni corrections. All participants will be matched on race and sex due to their relationships with 
pain and cognitive outcomes. All statistical analyses employed in this study were performed using 
SPSS (IBM) version 28.0 (IBM; Armonk, NY). Specific to hypotheses 1a-d: Sequential hierarchical 
multiple regression models will be employed to investigate the extent to which the continuous DII 
variable is associated with (H1a) greater severity, duration, and frequency of experimental and clinical 
pain outcomes, (H1b) accelerated epigenetic aging, and (H1c) worse cognitive decline between 
individuals with and without pain. Analyses of Variance (ANOVAs) will be performed in order to examine 
differences in variables of interest between groups: high-impact chronic pain, low-impact pain, and pain 
free controls.  Additionally, three separate sequential hierarchical regression models within each group 
will be used to examine the extent to which higher scores DII scores are associated with epigenetic 
aging and cognitive outcomes. Variables of interest (DII, epigenetic age, cognitive status) will be 
entered into step 1 of the analysis, relevant clinical covariates (e.g., BMI, smoking) will be entered in 
step 2 of the hierarchical regression models, and relevant demographic variables (i.e., age, race, sex, 
etc.)  in step 3 of the regression models. Finally, a modified Poisson-regression analysis will be 
performed to assess the relative risk of clinical cognitive impairment between pain impact groups.    
  
7. Possible Discomforts and Risks  
  
Equipment used in this research meet all current safety standards, and all research staff will be highly 
trained in the use of all equipment. This study may include risks that are unknown at this time. Potential 
risks for this study are related to use of study product, neuroimaging, blood draw procedure, blood 
pressure measurement, the physical performance tests, the cognitive function tests, the sensory 
testing, and potential loss of confidentiality related to study participation, as discussed in detail below.   
  
All assessment will be conducted at the Pain Clinical Research Unit (Dental Tower) and all sessions 
will be conducted by trained and certified research staff, which will monitor potential adverse 
experiences and symptoms. We will do safety labs within 48 hours if participant withdraws due to 
potential adverse effects to study drug (feeling weak/tired/low energy or changes in mental status). 
During the testing sessions, a fully equipped defibrillator is available along with a semi-automated ECG 
cart. All personnel associated with the study have received CPR training and training on management 
of acute events including syncope, chest pain, acute dyspnea, focal neurological symptoms and 
abnormal vital signs. Portable defibrillators are available at the assessment site. Additionally, a study 
physician is available on call and contact numbers for emergency services are posted. Institutional and 
community EMS services will be activated if needed. If participants develop chest pain, shortness of 
breath, or dizziness at any point during a screening or assessment visit, they will be instructed to rest 
and to contact the center and their physicians if these symptoms persist or recur.   
  

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Additionally, the study physician is available on call and contact numbers for emergency services are 
posted. Institutional and community EMS services will be activated if needed. If participants develop 
chest pain, shortness of breath, or dizziness at any point during a screening or assessment visit, they 
will be instructed to rest and to contact the center and their physicians if these symptoms persist or 
recur.  
  
Participants will be instructed to talk with the investigators about any discomforts that occur during the 
study. If for any reason the participant reports an injury, chest pain, leg swelling or pain, excessive 
shortness of breath, abnormal heart rhythm or dizziness, they will be referred to their doctor, or the PIs 
will call the doctor or other health care provider.   
  
Prior to beginning data collection, all study coordinators undergo standardized training on all study 
procedures. A detailed checklist for each data collection element is in place to ensure all study 
coordinators are appropriately trained and able to conduct study procedures. Research coordinators 
will be certified in each element of the study visit including obtaining informed consent, administering 
questionnaires, protecting confidentiality of collected data, performing the test batteries. Any study 
coordinator who is found to not adhere to all aspects of the protocol will be required to complete 
additional training followed by re-certification.   
  
All research staff complete human subjects training required by The University of Florida institutional 
review board (IRB) and National Institutes of Health (NIH). This training includes education about the 
importance of maintaining confidentiality of personal health information. The study principal 
investigators or a co-investigator will be available to answer questions that arise during the informed 
consent process as needed. More information about specific protective measures against risk is 
outlined below.  
  
Laboratory tests. Participants will have blood drawn at screening and during the post-intervention visit 
to measure their blood chemistry and will provide urine samples for osmolality tests. Abnormal results 
will be brought to the principal investigator’s attention immediately. The results will be reviewed and 
signed by the study clinician and Drs. Strath and Cruz-Almeida. If a participant has both low sodium 
(<134mEq/L) and high osmolality (>1200L), we will conduct a second blood test. If the sodium is again 
low (<134mEq/L) in the repeat blood draw, the participant will be excluded.  
  
Assessment of Adverse Events. A standard operating procedure will be established which is followed 
to collect and deal with adverse events during the research project. In particular, adverse events will 
be systematically monitored both during the sessions. In particular, participants will respond to a side 
effect check list to detect any possible physiological reactions related to the drug administration. This 
will include series of open-ended questions asked by trained research staff regarding any adverse 
events that have occurred since the last visit or phone contact. Open questions about pain 
experienced in various parts of the body will be delivered by study staff. Additionally, participants will 
be asked to the WOMAC and PANAS questionnaires to assess pain and feelings. This report will be 
reviewed by the principal investigator and study physician in a timely fashion. Any serious untoward 
event, whether related or unrelated to the study drug or procedures, will be reported to the UF IRB 
immediately as per their regulations.   
  
Adverse events will be defined as any physical symptoms or side effects that began following session 
commencement. All reported and observed adverse events will be tracked in a running adverse 
events participant log, which will contain information regarding dates, description, and severity. All 
adverse events will be coded using the most current version of the Medical Dictionary for Regulatory 

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Protocol:  IRB201801467 (UCOPE Study) 
 
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Activities (MedDRA). The number and percentage of participants reporting treatment-emergent 
adverse events will be tabulated by treatment, system organ class and MedDRA-preferred 
term. Treatment-emergent adverse events will be those adverse events that begin or worsened 
following the first dose of study drug. Adverse events will be further classified by severity and 
investigator-assigned relationship to the study variable. All reported and observed adverse events will 
be tracked on a running adverse events log (specific to each subject and maintained in his/her study 
file) and will contain information regarding onset/offset dates, time course (i.e., single, sporadic), 
severity, action taken regarding study drug, relationship to study drug, and whether it meets FDA 
criteria for “Serious.” Each reported event is reviewed by the principal investigator and the study 
physician in a timely fashion. Additionally, the principal investigator reviews all adverse events 
recorded in each participant’s log at the conclusion of study participation.    
  
In Case of Emergency. Participants will have 24-hour access to emergency care and will be provided 
with a means of contacting the on-call study doctor and research staff. Participants will be informed 
and encouraged to contact the study physician and study staff immediately with medical concerns or 
unusual reactions. Participants will also be informed of the closest Emergency Department location to 
their residence.   
  
Data and Safety Monitoring Plan. A Data Safety Monitoring Plan will be in place. In particular, the 
following procedures will be implemented to ensure data and participant safety. Study progress and 
safety will be reviewed by the principal investigators in collaboration with Dr. Roland Staud, M.D., the 
study MD, and Dr. Feifel, M.D., Ph.D., the sponsor of the IND and consultant on the project. The 
Independent Safety Monitor for this study will consist of an established senior investigator not associated 
with our study. A study end report will be compiled and will include a list and summary of adverse events. 
In addition, this report will address: (1) whether adverse event rates are consistent with pre-study 
assumptions; (2) reason for dropouts from the study; (3) whether all participants met entry criteria; (4) 
whether continuation of the study is justified on the basis that additional data are needed to accomplish the 
stated aims of the study; and (5) conditions whereby the study might be terminated prematurely. The annual 
report will be signed by the Independent Safety Monitor and will be forwarded to the IRB, NIH, and FDA. 
The Data Safety Monitoring Plan will also require that all significant serious adverse events that may be 
possibly related to the study participation will be reported to the IRB, FDA, and NIH within 48 hours of the 
principal investigators learning of the event. In addition, any unanticipated serious adverse events that may 
increase the risk of the research for participants or potential participants will be reported to the IRB and the 
NIH within 48 hours of the principal investigators being informed about the event. This study will be stopped 
prior to its completion if: (1) the intervention is associated with adverse effects that significantly impact the 
risk-benefit ratio, (2) study recruitment or retention becomes futile, (3) any new information becomes 
available during the trial that necessitates stopping the trial; or (4) if independent safety monitor indicates 
stopping trial is necessary due to adverse event frequency or severity.  
  
ClinicalTrials.gov Requirements. In accordance with Public Law 110-85 and NIH guidelines, the 
proposed research will be registered with ClinicalTrials.gov prior to commencement of study 
procedures involving participants.  
  
Blood Draw  
The risks of drawing blood from a vein include discomfort at the site of puncture; possible bruising and 
swelling around the puncture site; rarely an infection; and, uncommonly, faintness from the procedure.  
  
Blood Pressure Measurement  
The risks of placing a blood pressure cuff on a participant’s arms are that it may cause pinching or 
slight bruising.    

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Physical Tests  
There is a risk of losing balance and falling or development of chest discomfort due to coronary 
ischemia or dyspnea due to heart failure or lung disease associated with the physical performance-
based testing (e.g., the ¼ mile walk test, balance tests, rising from a chair). We will minimize this risk 
by: (1) safely escorting participants to chairs located along the walking course should they become 
unsteady; (2) following participants at a close distance; and, (3) being at participants’ side should they 
need assistance. Research staff members will be trained in the conduct of the physical performance 
tests before they work with study participants. Study staff members are trained not to perform these 
tests if they feel that testing is unsafe. In addition, participants will be asked whether they feel the test 
is safe. Those who state it may be unsafe will not be allowed to complete the test. Staff members will 
be trained to protect against falling and will be trained in CPR. They will be trained in activating the 
emergency response system at the research facility.    
  
Sensory Testing  
The sensory testing procedures may be uncomfortable or unpleasant, in that participants may 
experience 
some 
temporary 
discomfort 
from 
the 
thermal, 
pressure, 
and 
mechanical 
stimulation. However, if the participants feel the sensation is greater than they wish to tolerate, they can 
stop any of the procedures at any time.  
  
Personal Information  
Some of the questions participants will be asked may be personal in nature and may make participants 
feel uncomfortable. Time will be made to talk with the participant if they appear to be distressed. We 
will be asking for information about sensitive issues, such as mood and thoughts of suicide which may 
make participants feel uncomfortable. If they are uncomfortable answering these questions, they can 
choose not to answer and discontinue participation in the study. Some people, when asked such 
questions, experience strong emotional reactions that may require counseling. If they do, they are 
strongly encouraged to tell the Principal Investigator, who can make an appropriate referral to the 
Psychology Clinic or to the UF Counseling & Wellness Center at (352) 392-1575. If we find that the 
participant is suicidal, he/she will be excluded from further participation in the study and an appropriate 
referral will be made. If we should discover, based on the questionnaires or formal clinical interview, 
that the participant experiences marked depression or suffer from another psychiatric condition, we will 
offer to make an appropriate medical, psychiatric, and/or psychological referral.  
   
Confidentiality  
Data that will be collected from human subjects for this project will include behavioral performance 
measures, rating scales assessed through interviews and patients’ responses to self-rated scales, 
physiological, and neuroimaging data. Data will be collected specifically for the proposed research 
project. Access to individually identifiable private information about human subjects will be limited to 
research staff affiliated with the project. Research records will be kept confidential to the extent provided 
by law. The collection and submission of medical information will be accomplished with strict adherence 
to professional standards of confidentiality. Participants’ medical information will be kept in a secure 
location accessible only to research staff associated with this study. Participants will only be identifiable 
by ID number, and any published findings resulting from the study will not refer to or identify individuals. 
A number of methods will be employed to maintain confidentiality of participants. First, data will be 
collected in secure spaces where the session cannot be overheard. Secondly, only study investigators 
and key research staff (i.e. data manager and study programmers) will have access to the study 
database. Third, participants will be assigned a unique study identifier. Individual names are not linked 
with collected data in the password-protected study database and only the unique study identifier will 

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be used. A file linking the participant name and contact information and their specific study identifier 
will be kept separately and will be password protected and only accessible to study team members. 
Fourth, collected data will be maintained in locked computer files and file cabinets to which only study 
team members have access. Collected data will be used only for research purposes. Published data 
will not contain any individual identifiers. Finally, all research staff members have to retake refresher 
course certification exams every year.  
  
Informed Consent  
Prior to entry in the trial, the investigator(s) or study coordinator(s) will explain to potential participants 
the aims, methods, reasonably anticipated benefits, and potential hazards of the trial and any 
discomfort it may entail. Subjects will be informed that their participation in the study is entirely 
voluntary and that they may withdraw consent to participate at any time. They will be told that 
competent physicians/lab personnel will examine their records but that personal information will be 
treated as strictly confidential and will not be publicly available. Subjects will be given the opportunity 
to ask questions and will be given sufficient time to review all of the relevant information associated 
with the study. After this explanation and before entry to the trial, the subject’s consent will be obtained 
and documented via signature of an informed consent form by both the subject and the person 
conducting the informed consent discussion. If signed informed consent cannot be obtained, the 
subject will not be included in the trial.   
  
Inclusion of Women and Minorities/ Inclusion of Children  
Men and women will be approximately equally represented in the sample. No clear evidence exists yet 
that OT levels vary between cultures. However, prosocial behavior associated with the OT system, 
have been shown to vary by culture (Kim et al., 2010). In addition, there is evidence that OT-related 
polymorphisms may vary across culture (Liu et al., 2010). Based on these empirically supported 
considerations we will enter race/ethnicity as covariate into our statistical models.   
  
The proposed research will address effects of OT on pain, cognition, inflammation, and physical 
health in older men and women. Children are not the focus of this project, and by design, children will 
not be included in the study.  
  
8. Possible Benefits  
  
There are no direct benefits for study participation. There may be benefits that we are not yet aware of. 
The report about the results of the study will be made available to study participants as well as others 
in the community. However, the greatest benefit will be to society as a whole. Scientific knowledge 
advances slowly, but study results will increase our understanding of pain and cognition in aging. Such 
knowledge may be implemented in intervention programs that may have the potential to increase 
function and personal well-being.   
  
9. Conflict of Interest  
  
There are no conflicts of interest with this project.   
  
  
  
 
 
 

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References Cited (UCOPE):  
  
Ahmed, M. A., & Elosaily, G. M. (2011). Role of oxytocin in deceleration of early atherosclerotic 
inflammatory processes in adult male rats. International Journal of Clinical and Experimental 
Medicine, 4, 169-178.  
Alexander, N. B., & Hausdorff, J. M. (2008). Linking Thinking , Walking , and Falling. Journal of  
Gerontology, 63A(12),1325–1328.  
Ansseau, M., Legros, J., Mormont, C., Cerfontaine, J., Papart, P., Geenen, V., Adam, F., & Franck, 
G. (1987). Intranasal oxytocin in obsessive-compulsive disorder. Psychoneuroendocrinology, 12, 
231-236.  
Anton, S. D., Manini, T. M., Milsom, V. A., Dubyak, P., Cesari, M., Cheng, J., Daniels, M. J., 
Marsiske, M., Pahor, M., Leeuwenburgh, C., & Perri, M. G. (2011). Effects of a weight loss plus 
exercise program on physical function in overweight, older women: A randomized controlled trial. 
Clinical Interventions in Aging, 6, 141-149.  
Arletti, R., Benelli, A., Poggioli, R., Luppi, P., Menozzi, B., & Bertolini, A. (1995). Aged rats are still 
responsive to the antidepressant and memory-improving effects of oxytocin. Neuropeptides, 29, 
177-182.  
Arsenijevic, Y., Dreifuss, J. J., Vallet, P., Marguerat, A., & Tribollet, E. (1995). Reduced binding of 
oxytocin in the rat brain during aging. Brain Research, 698, 275-279.  
Ashton, M. C., & Lee, K. (2007). Empirical, theoretical, and practical advantages of the HEXACO 
model of personality structure. Personality and Social Psychology Review, 11(2), 150-166. doi: 
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