Cannabidiol for Bilateral Total Knee Arthroplasty

Study Overview
=================
Brief Summary
-----------------
In light of the opioid epidemic and evidence suggesting that cannabis may be opioid-sparing, we are in a unique position to conduct a novel, high-impact study that would set the stage for future RCTs examining the effects of a nonintoxicating and nonaddictive cannabinoid in an orthopedic patient population. Epidiolex®, an oral cannabidiol (CBD) solution, is the first ever cannabis-derived medication to be approved by the Food & Drug Administration. Our aim is to conduct a pilot study using a placebo oral solution, 400mg and 800mg Epidiolex® to gather data on its effects on patients undergoing bilateral total knee arthroplasty (BTKA). We will be estimating whether Epidiolex® is associated with minimal opioid use and adequate analgesia. We will also assess its tolerability, pharmacokinetics, and effects on inflammatory markers in the perioperative setting.

Official Title
-----------------
Effects of Cannabidiol (CBD) Oral Solution in Patients Undergoing Bilateral Total Knee Arthroplasty: a Randomized, Controlled, Parallel, Triple Blind, Pilot Study

Conditions
-----------------
Pain, Postoperative, Opioid Use, Knee Osteoarthritis

Intervention / Treatment
-----------------
* Drug: cannabidiol
* Other: Ora-sweet SF


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Age 18 to 75 Scheduled for same-day bilateral total knee replacements with participating surgeons American Society of Anesthesiologists (ASA) Physical Status 1 or 2 Exclusion Criteria: ASA 3 and higher Weight < 40kg Planned use of general anesthesia Contraindication to major components of study protocol Cannabis or cannabinoid use within the past 3 months (recreational and/or medical) Use or ingestion of hemp seeds or hemp oil in any form within the past 30 days Chronic opioid use (>3 months) Coumadin use Current use of SSRI or SNRIs History of substance abuse or dependence Active or history of major psychiatric illness Severe cardiovascular disorder Severe hepatic or renal insufficiency (transaminase levels above ULN) History of epilepsy Diagnosis of rheumatic disease, autoimmune disease, or immunodeficiency (e.g. rheumatoid arthritis, psoriatic arthritis, inflammatory bowel disease, multiple sclerosis, etc.) Use of valproate or clobazam Known or suspected hypersensitivity, allergy, or contraindication to cannabinoids or any of the excipients in the study medications (i.e. sesame oil, sucralose, strawberry flavor) Active use of steroids - oral steroids upon admission Stress dose steroids Non-English speakers

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Ora-sweet SF<br> | Other: Ora-sweet SF<br>* Ora-sweet SF placebo<br>|
| Experimental: 400mg cannabidiol<br> | Drug: cannabidiol<br>* Epidiolex (cannabidiol) oral solution<br>* Other names: Epidiolex;|
| Experimental: 800mg cannabidiol<br> | Drug: cannabidiol<br>* Epidiolex (cannabidiol) oral solution<br>* Other names: Epidiolex;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cumulative Opioid Usage in First 72 hours Postoperatively | Cumulative opioid usage over the first 72 hours after surgery. Measured in morphine equivalents (ME), a scale that measure opioid usage among all opioid medications | 0-72 hours postoperatively | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetics of CBD | Levels of CBD in the blood. This is measured using blood draws and lab analysis. | 0, 1, 2, 3, 4, 6 hours after medication administration | 
| Levels of Plasma Inflammatory Marker Interleukin-6 | Interleukin-6 (IL6) is an inflammatory marker found in plasma. The levels of IL6 are measured using blood draws and lab analysis. | Preoperative, Postoperative day 1 | 
| NRS Pain at rest | Pain at rest measured using numerical rating scale(NRS) from 0-10, with 0 being no pain at all to 10 being the worst pain imaginable. | Preoperatively; postoperatively in the PACU, morning of postoperative day (POD) 1,2,3,4,7 and at 3 months | 
| NRS Pain with movement | Pain with movement using numerical rating scale(NRS) from 0-10, with 0 being no pain at all to 10 being the worst pain imaginable. | Preoperatively; morning of postoperative day (POD) 1,2,3,4,7 and at 3 months | 
| Brief Pain Inventory Short Form | Brief Pain inventory short form measures the severity of pain and its impact on function. It measures pain from 0-10 0 being no pain whatsoever to 10 being the worst pain imaginable. It measures impact on function from 0-10, 0 being no impact whatsoever to 10 being completely impactful. | Preoperatively; morning of postoperative day (POD) 1,2,3,4,7 and at 3 months | 
| Incidence of adverse events | Adverse events, including allergic reactions, pyrexia (fever), somnolence (excessive sleepiness), GI problems (upset stomach, diarrhea), dry mouth, escalation of post-operative opioid requirement | Postoperatively in the PACU; morning of postoperative day (POD) 1,2,3,4,7 and at 3 months | 
| Opioid related Symptom Distress Scale (ORSDS) | ORSDS measures opioid related side effects. There are 13 side effects with 3 subcategories (severity, frequency, bothersomeness) each with 5 different responses (scored 0-4). | Morning of postoperative day (POD) 1,2,3,4,7 and at 3 months | 
| Anxiety levels | Hospital Anxiety and Depression Scale (HADS) asks 14 questions, 7 about anxiety and 7 about depression. Responses are scored from 0-3. Responses between the two categories are summed and scoring is as follows: 0-7 = normal, 8-10=borderlines abnormal, 11-21=abnormal | Preoperatively; Morning of postoperative day (POD) 1,2,3,4,7 and at 3 months | 
| Cumulative inpatient analgesic use (non-opioid) | Total non-opioid medication usage | POD0 - POD3 | 
| Opioid & non-opioid analgesic consumption | Total opioid & non-opioid medication usage | At hospital discharge to POD7 and at 3 months | 
| Hospital length of stay | Length of stay measured in hours | End of surgery to hospital discharge | 
| Blinding Assessment | Patients are asked which treatment they think they received. The correctness of their guesses is then measured using the bang-blinding index to see if patients were able to accurately guess which treatment they received. It is measured on a scale of -1 to 1. Scores closer to 0 indicate better blinding, or patients not being able to guess their treatment | POD4 | 
| Time to reach discharge physical therapy goals | Physical therapy goals for total knee replacement include walking 100 feet, going up and down 4 stairs, and independent transfer (meaning they can move from a lying to standing position independently). Patients need to complete these goals before being discharged | At hospital discharge - up to 3 days after surgery | 
| Range of motion | Range of motion, or extension and flexion of the knees, are measured preoperatively and at the patients' 6 week surgeon visit. It is measured in degrees | preoperatively, 6 weeks postoperatively. | 
| Sleep quality and duration | Sleep quality assessed by actigraphy using ActiGraph wGT3X-BT activity monitor | POD0 - POD3 | 
| Sleep quality | Sleep quality assessed by Leeds sleep evaluation questionnaire (LSEQ). Responses to 10 questions will be measured on a slider scale ranging from 0-100. | preoperatively; morning of postoperative day (POD) 1,2,3,4,7 and at 3 months |