Cannabidiol for Pain Management After Knee Replacement

(CORK Trial)

Recruiting at 1 trial location

Overseen By Katherine Nowak

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Chad Brummett

Must not be taking: Valproate, Clobazam, Warfarin, others

Disqualifiers: Illicit drug use, Neurological disorders, Cancer, Uncontrolled diabetes, others

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 1

380 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but it does exclude those using certain drugs like valproate, clobazam, warfarin, and strong inducers of specific liver enzymes. It's best to discuss your current medications with the study team to see if they might affect your eligibility.

What data supports the effectiveness of the drug Cannabidiol (CBD) for pain management after knee replacement?

The study titled 'Topical Cannabidiol (CBD) After Total Knee Arthroplasty Does Not Decrease Pain or Opioid Use' found that CBD did not provide pain relief or reduce opioid use after knee replacement surgery. ^{1 2 3 4 5}

Is cannabidiol (CBD) safe for use in humans?

Research shows that cannabidiol (CBD) is generally safe for human use, with studies indicating no significant difference in adverse events between CBD and placebo groups. However, more research is needed to fully understand its safety profile, especially in the context of pain management after knee replacement. ^{1 6 7 8 9}

How does the drug Cannabidiol (CBD) differ from other treatments for pain management after knee replacement?

Cannabidiol (CBD) is unique because it is a non-psychoactive compound derived from cannabis, and it is being explored for its potential to manage pain without the side effects associated with opioids. Unlike traditional pain medications like opioids or NSAIDs, CBD is thought to work by interacting with the body's endocannabinoid system, which may help reduce inflammation and pain. ^{1 10 11 12 13}

What is the purpose of this trial?

The goal of this study is to better understand how daily treatment with cannabidiol (CBD) affects the need for opioid pain medication, as well as pain, inflammation and other related symptoms, after knee replacement surgery. The information collected in this study is necessary to help understand whether CBD may be a useful medication before and/or after surgery. The study hypothesis is that CBD exerts opioid-sparing effects through anti-inflammatory, analgesic, and anxiolytic mechanisms.

Research Team

Chad Brummett, MD

Principal Investigator

University of Michigan

Kevin F Boehnke

Principal Investigator

University of Michigan

Eligibility Criteria

This trial is for adults who have had a knee replacement surgery due to osteoarthritis and are in need of pain management. Participants should not be currently using CBD or cannabis products, must not have allergies to cannabinoids, and should not be on certain medications that could interact with CBD.

Inclusion Criteria

My main diagnosis is knee osteoarthritis.

I am scheduled for a first-time knee replacement surgery.

Willing and able to read, understand, and sign the informed consent (English)

Exclusion Criteria

I have a serious illness or significant lab results.

Medical or psychiatric conditions that in the judgment of study personnel would preclude participation in this study

Any impairment, activity, behavior, or situation that in the judgment of the study team would prevent satisfactory completion of the study protocol

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Pre-operative Treatment

Participants receive either CBD or placebo prior to surgery

1 week

1 visit (in-person)

Post-operative Treatment

Participants receive either CBD or placebo after surgery

5 weeks

Weekly visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Cannabidiol

Trial Overview The study is testing whether taking cannabidiol (CBD) orally can reduce the need for opioid painkillers after knee surgery. Patients will either receive Epidiolex, a CBD solution, or a placebo without knowing which one they're getting.

Participant Groups

Group I: Pre-operative placebo plus post-operative CBD Experimental Treatment 2 Interventions

Participants will take placebo prior to surgery days 1-7, then days 8-36 participants will take CBD 300 milligrams (150mg twice a day \[b.i.d.\])

Group II: Pre-operative CBD plus post-operative placebo Experimental Treatment 2 Interventions

Participants will take CBD 300 milligrams (mg) /day prior to surgery on days 1-7 (150mg twice a day \[b.i.d.\]), then days 8-36 will take placebo twice a day \[b.i.d.\]

Group III: Pre - and post-operative CBD Experimental Treatment 1 Intervention

Participants will take 300 milligrams (mg)/day on days 1-36 (150mg twice a day \[b.i.d.\])

Group IV: Pre- and post-operative placebo Placebo Group 1 Intervention

Participants will take placebo on days 1-36 twice a day \[b.i.d.\]

Cannabidiol is already approved in United States, European Union, Canada for the following indications:

Approved in United States as Epidiolex for:

• Seizures associated with Lennox-Gastaut syndrome
• Seizures associated with Dravet syndrome
• Seizures associated with tuberous sclerosis complex

Approved in European Union as Epidiolex for:

• Seizures associated with Lennox-Gastaut syndrome
• Seizures associated with Dravet syndrome
• Seizures associated with tuberous sclerosis complex

Approved in Canada as Epidiolex for:

• Seizures associated with Lennox-Gastaut syndrome
• Seizures associated with Dravet syndrome

Who Is Running the Clinical Trial?

Chad Brummett

Lead Sponsor

Trials

1

Recruited

380+

National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)

Collaborator

Trials

508

Recruited

1,090,000+

Findings from Research

In a study involving 80 patients who underwent total knee arthroplasty, topical CBD did not provide additional pain relief or reduce opioid consumption compared to a placebo, indicating it may not be effective for postoperative pain management.

The CBD group actually reported higher pain scores on postoperative day 2 compared to the essential oil group, suggesting that topical CBD may not be beneficial in the context of multimodal analgesia following surgery.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Topical Cannabidiol (CBD) After Total Knee Arthroplasty Does Not Decrease Pain or Opioid Use: A Prospective Randomized Double-Blinded Placebo-Controlled Trial. Haffar, A., Khan, IA., Abdelaal, MS., et al.[2022]

Intra-articular administration of 10 mg of morphine after total knee arthroplasty significantly reduced pain severity in the first 6 hours post-surgery compared to a control group receiving saline.

Patients receiving morphine also experienced a longer time before needing additional pain relief and consumed less analgesics in the first 24 hours, with no increase in side effects compared to the control group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Analgesic efficacy of the intra-articular administration of high doses of morphine in patients undergoing total knee arthroplasty. Garcia, JB., Barbosa Neto, JO., Vasconcelos, JW., et al.[2019]

Oral dexamethasone significantly reduced postoperative pain scores in patients undergoing total knee arthroplasty, particularly on postoperative days 2, 3, and 4, compared to a placebo group.

Despite the pain reduction, there were no significant differences in opioid usage, nausea, vomiting, or other complications between the dexamethasone and placebo groups, suggesting a favorable safety profile for this treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The AAHKS Clinical Research Award: Oral Dexamethasone Following Total Knee Arthroplasty: A Double-Blind, Randomized Controlled Trial. Shaw, JH., Wesemann, LD., Banka, TR., et al.[2023]

Applying a buprenorphine transdermal patch directly to the knee of osteoarthritis patients resulted in a significant reduction in pain, as measured by the Numeric Rating Scale (NRS), compared to applying the patch on the chest.

The knee application method also had fewer adverse effects (19.32% vs. 64.00% for chest application) and higher patient compliance (82.95% vs. 37.60%), suggesting it is a safer and more effective option for managing knee OA pain.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Novel Application of Buprenorphine Transdermal Patch to Relieve Pain in the Knee Joint of Knee Osteoarthritis Patients: A Retrospective Case-Control Study. Gil, HY., Park, S., Kim, NE., et al.[2020]

In a study of 45 patients undergoing bilateral total knee arthroplasty, the addition of steroids to local infiltration analgesia significantly reduced pain levels and improved rehabilitation outcomes compared to LIA without steroids, particularly in the first week post-surgery.

Steroid-treated knees showed better range of motion and quicker recovery of active straight leg raises, with no increase in complications or adverse effects observed over a 1-year follow-up period.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of Steroid in Local Infiltration Analgesia in One-Stage Bilateral Total Knee Arthroplasty: A Paired-Randomized Controlled Study. Chan, VWK., Chan, PK., Yan, CH., et al.[2022]

In a study of 109 patients who underwent total hip or knee replacement surgeries, 22% reported using cannabidiol (CBD) during their treatment period.

Despite the prevalence of CBD use, there was no significant difference in pain satisfaction between those who used CBD and those who did not, indicating a need for further research on the safety and efficacy of CBD in this context.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rates of self-directed perioperative cannabidiol use in patients undergoing total hip or knee arthroplasty. Yu, JS., Premkumar, A., Liu, S., et al.[2021]

In a study of 195 patients undergoing total hip and knee arthroplasty, 16.4% reported using CBD/THC products during the perioperative period, with higher usage in knee arthroplasty patients (22.6%) compared to hip arthroplasty patients (11.7%).

Despite the use of CBD/THC products, there was no significant difference in opioid consumption, pain scores, or length of hospital stay between users and non-users, suggesting that these products may not significantly impact post-operative opioid requirements.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Use of Tetrahydrocannabinol and Cannabidiol Products in the Perioperative Period Around Primary Unilateral Total Hip and Knee Arthroplasty. Runner, RP., Luu, AN., Nassif, NA., et al.[2021]

Cannabidiol (CBD) has shown potential therapeutic effects for pain and inflammation, but the evidence is inconclusive due to variations in study methods, including different routes of administration and types of pain assessed, with most studies involving small participant numbers.

Positive results were consistently observed in studies focusing on the effects of CBD on arthritis, suggesting it may be particularly beneficial for this condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of Cannabidiol in Inflammation: A Review of Pre-clinical and Clinical Findings. Sklenárová, M., Šíma, M., Slanař, O.[2023]

In a randomized, double-blind, placebo-controlled trial involving 136 patients with hand osteoarthritis or psoriatic arthritis, cannabidiol (CBD) did not show a significant reduction in pain intensity compared to placebo after 12 weeks of treatment.

The study found no meaningful effects of CBD on secondary outcomes such as sleep quality, anxiety, or depression, indicating that CBD may not be an effective add-on therapy for pain management in these conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cannabidiol treatment in hand osteoarthritis and psoriatic arthritis: a randomized, double-blind, placebo-controlled trial. Vela, J., Dreyer, L., Petersen, KK., et al.[2022]

In a study of 150 patients undergoing arthroscopic ACL reconstruction, intra-articular injection of 5 mg morphine significantly reduced postoperative pain compared to a placebo, leading to lower analgesic requirements in the first 12 hours after surgery.

Morphine was found to be the most effective pain reliever among the opioids tested, while methadone showed the least response, suggesting that morphine is a valuable addition to local anesthetics for pain management in knee surgery.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The comparison effects of intra-articular injection of different opioids on postoperative pain relieve after arthroscopic anterior cruciate ligament reconstruction: A randomized clinical trial study. Arti, H., Mehdinasab, SA.[2022]

In a study of 160 patients undergoing total knee arthroplasty, the transdermal buprenorphine (TDB) patch provided significantly better pain relief compared to oral celecoxib, as indicated by lower visual analogue scale (VAS) scores during rest and activity at multiple time points post-surgery.

Patients using the TDB patch required less morphine for pain management and showed improved functional recovery, with greater range of motion and higher Lysholm scores, all without an increase in adverse events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Transdermal buprenorphine patch versus oral celecoxib for pain management after total knee arthroplasty: An open- label, randomized controlled trial. Xu, X., Xie, L., Liu, H., et al.[2021]

In a pilot study, patients who received local infiltration analgesia combined with anti-hyperalgesic drugs (pregabalin and s-ketamine) achieved an average knee flexion of 88.5 degrees by the second postoperative day, indicating effective pain management and improved mobility after total knee arthroplasty.

The side effects of this drug combination were mild and mostly self-limiting, suggesting that the method is safe for patients in the early postoperative period.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The effect of addition of pregabalin and s-ketamine to local infiltration analgesia on the knee function outcome after total knee arthroplasty. Kadic, L., Niesten, E., Heijnen, I., et al.[2015]

In a study of 60 patients undergoing total knee arthroplasty, both pregabalin and duloxetine significantly reduced pain and the need for additional pain relief within the first 48 hours after surgery compared to a placebo.

However, neither medication had a significant impact on long-term knee mobility, as measured by the WOMAC score six months post-surgery.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of Perioperative Pregabalin and Duloxetine for Pain Management After Total Knee Arthroplasty: A Double-Blind Clinical Trial. Imani, F., Emami, A., Alimian, M., et al.[2023]

References

1. United States pubmed.ncbi.nlm.nih.gov

Topical Cannabidiol (CBD) After Total Knee Arthroplasty Does Not Decrease Pain or Opioid Use: A Prospective Randomized Double-Blinded Placebo-Controlled Trial. [2022]

2. Brazil pubmed.ncbi.nlm.nih.gov

Analgesic efficacy of the intra-articular administration of high doses of morphine in patients undergoing total knee arthroplasty. [2019]

3. United States pubmed.ncbi.nlm.nih.gov

The AAHKS Clinical Research Award: Oral Dexamethasone Following Total Knee Arthroplasty: A Double-Blind, Randomized Controlled Trial. [2023]

4. Switzerland pubmed.ncbi.nlm.nih.gov

A Novel Application of Buprenorphine Transdermal Patch to Relieve Pain in the Knee Joint of Knee Osteoarthritis Patients: A Retrospective Case-Control Study. [2020]

5. Germany pubmed.ncbi.nlm.nih.gov

Effect of Steroid in Local Infiltration Analgesia in One-Stage Bilateral Total Knee Arthroplasty: A Paired-Randomized Controlled Study. [2022]

6. England pubmed.ncbi.nlm.nih.gov

Rates of self-directed perioperative cannabidiol use in patients undergoing total hip or knee arthroplasty. [2021]

7. United States pubmed.ncbi.nlm.nih.gov

Use of Tetrahydrocannabinol and Cannabidiol Products in the Perioperative Period Around Primary Unilateral Total Hip and Knee Arthroplasty. [2021]

8. Czech Republic pubmed.ncbi.nlm.nih.gov

Effects of Cannabidiol in Inflammation: A Review of Pre-clinical and Clinical Findings. [2023]

9. United States pubmed.ncbi.nlm.nih.gov

Cannabidiol treatment in hand osteoarthritis and psoriatic arthritis: a randomized, double-blind, placebo-controlled trial. [2022]

10. India pubmed.ncbi.nlm.nih.gov

The comparison effects of intra-articular injection of different opioids on postoperative pain relieve after arthroscopic anterior cruciate ligament reconstruction: A randomized clinical trial study. [2022]

11. France pubmed.ncbi.nlm.nih.gov

Transdermal buprenorphine patch versus oral celecoxib for pain management after total knee arthroplasty: An open- label, randomized controlled trial. [2021]

12. Belgium pubmed.ncbi.nlm.nih.gov

The effect of addition of pregabalin and s-ketamine to local infiltration analgesia on the knee function outcome after total knee arthroplasty. [2015]

13. Netherlands pubmed.ncbi.nlm.nih.gov

Comparison of Perioperative Pregabalin and Duloxetine for Pain Management After Total Knee Arthroplasty: A Double-Blind Clinical Trial. [2023]