Cannabidiol for Postoperative Opioid Reduction in Primary Total Knee Arthroplasty - a Randomized, Two by Two Factorial, Double-blind, Placebo-controlled Clinical Trial

Exclusion criteria

• Revision or bilateral total knee arthroplasty
• Individuals receiving or actively applying for worker's compensation or disability and other aspects associated with potential secondary gain (postoperative disability for recovery is permitted)
• Severe physical impairment or clinically significant illness (e.g., blindness, paraplegia)
• Co-morbid medical conditions that may significantly impair physical functional status (e.g., current non-skin malignancies, solid organ transplant in the past year)
• Illicit drug use (other than cannabis). Unreported opioid use would be exclusionary but reported prescribed opioid use is allowed (e.g. patient denies opioid use but is found to be positive on the urine drug screen)
• Self-reported use of cannabis products within the 7 days prior to starting study drug
• Self-reported use of cannabis products within the 8-30 days prior to starting study drug AND either a failed drug screen or inability to confirm successful washout (Note - may be rescreened with appropriate wash-out period)
• High daily preoperative opioid dose
• Individuals with major neurological disorders, such as dementia, Parkinson's disease, cognitive impairment, epilepsy, history of traumatic brain injury/head injury, and seizures
• Individuals with significant illness (e.g., cancer) and/or clinically significant labs (e.g. labs measured by complete blood count (CBC) and basic chemistry with values meaningfully outside of the normal range \[abnormal levels to be reviewed by the Principal Investigator or prescribing provider\])
• Medical or psychiatric conditions that in the judgment of study personnel would preclude participation in this study (e.g., psychosis, suicidal ideation; note that stable anxiety and depression are not exclusions)
• Pregnant or nursing women (total joint arthroplasty is typically not indicated in this group of patients)
• Self-reported liver cirrhosis
• Self-reported uncontrolled diabetes
• Self-reported active hepatitis (any etiology, including infectious, autoimmune, or alcohol-related)
• Blood pressure at screening above 180 millimeters of mercury (mmHg) systolic and/or 120 mmHg diastolic; if value exceeds the set point, potential participants will have repeat assessment within 5 minutes for up to two additional measurements.
• Resting heart rate at screening less than 50 beats per minute (bpm) or greater than 100 bpm; if value exceeds the set point, potential participants will have repeat assessment within 5 minutes for up to two additional measurements.
• Elevated liver enzymes and bilirubin (measured by blood test at screening)
• Serum total bilirubin ≥ 2.5 milligrams (mg) per deciliter (dL) (mg/dL); or,
• Alanine transaminase (ALT) or Alanine transaminase (AST) ≥ 3x upper limit normal (ULN); or,
• Alkaline phosphatase ≥ 2x ULN
• Severe cardiovascular disease (e.g., current unstable angina, current congestive heart failure, or current severe valvular abnormalities) that is self-reported by patient or in medical record
• Current valproate, clobazam, or warfarin use per self-report or medical records
• Current use of strong inducers of cytochrome p450 (CYP) enzymes CYP3A4 and CYP2C19, or CYP2C19 substrates with a narrow therapeutic index
• Self-reported allergies to sesame oil, strawberries, opioids, or cannabis/cannabinoids and confirmed by the investigator during screening
• Any impairment, activity, behavior, or situation that in the judgment of the study team would prevent satisfactory completion of the study protocol
• Self-reported severe side effects to opioids precluding the use of opioids for post-surgical pain and/or clear plan not to use any opioids after surgery and confirmed by the investigator during screening
• Participation in other clinical trials over the course of this study (note: outside of active period is permissible as determined by the investigator during screening)