Osteoarthritis (OA) represents a significant cause of disability worldwide and the knee is the most commonly affected joint. Oxytocin (OT) is a mediator of endogenous analgesia in animal and human studies. This proposal will test the efficacy and safety of self-administered intranasal OT over 4-weeks in older individuals relative to placebo (P) evaluating its effects on pain and function in aging and testing potential underlying neurobiological mechanisms.

Osteoarthritis 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 osteoarthritis has been traditionally attributed to peripheral mechanisms, but measures of joint damage only modestly account for the presence or severity of osteoarthritis-related pain. The neuropeptide oxytocin has been recognized as a mediator of endogenous analgesia in animal and human studies. However, little is known about the neurobiological mechanisms underlying oxytocin's pain-relieving properties.

This study will test the efficacy and safety of self-administered intranasal oxytocin over 4-weeks in older individuals with knee osteoarthritis. Relative to placebo, daily administration of intranasal oxytocin diminished self-reported pain, physical and emotional functioning and changes in brain metabolite concentrations. With strong support from the University of Florida and the McKnight Brain Institute, this interdisciplinary project, using a comprehensive multi-methods approach, will be the first to determine the potential benefit of oxytocin as a novel analgesic therapy for knee osteoarthritis pain in aging.

Inclusion Criteria:

• knee osteoarthritis/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 Visual Descriptor Scale), and who have elevated levels of plasma Imterleukin-6 (>2.5 pg/ml) will be considered for participation.

Exclusion Criteria:

• 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,
• low sodium and high osmolality levels,
• 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),
• gastroparesis.
• individuals with heart problems (e.g., cardiomyopathy, history of myocardial infarction, arrhythmias, prolonged QT interval)
• Participants will also be excluded if they have concurrent medical or arthritic conditions that could confound symptomatic knee osteoarthritis-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%);
• neurological disease (e.g., Parkinson's, Multiple Sclerosis);
• 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., Montreal Cognitive Assessment score < 25)]; and
• 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 seizures].
• pregnant individuals will be excluded

During each 4-week treatment period (8 weeks total across both crossover periods)

Adverse events were collected systematically via weekly telephone symptom checklists during each 4-week treatment period. Participants reported the presence and severity of 45 predefined symptoms. Serious adverse events were defined per FDA criteria (death, life-threatening, hospitalization, persistent disability, or medically important event).