Cannabinoids vs. Placebo on Persistent Post-surgical Pain Following TKA: A Pilot RCT

The Effect of Cannabinoids vs. Placebo on Persistent Post-surgical Pain Following Total Knee Arthroplasty: A Multicenter, Randomized Pilot Trial

Each year, approximately 75,000 Canadians undergo knee replacement surgery, and up to 25% develop persistent post-surgical pain. Persistent post-surgical pain is associated with depression, anxiety, unemployment, and reduced quality of life. Chronic pain after surgery is often managed with opioid therapy, which typically provides only modest benefits and is associated with rare but serious adverse events, such as overdose and death. A number of studies have found that greater pain just before and after knee replacement surgery is associated with the development of chronic pain, suggesting that reducing peri-operative pain may help prevent persistent post-surgical pain.

Medicinal cannabis has begun to emerge as a potential therapy for pain reduction, and produces effects largely due to 2 active components: (1) cannabidiol (CBD), and (2) tetrahydrocannabinol (THC). Studies of CBD have shown analgesic, anti-inflammatory, and anti-anxiety properties, but without the psychoactive effects (feeling 'high') that THC produces. This study will assess the feasibility of a definitive trial to explore whether adding CBD dominant vs. placebo to usual care before and after surgery can reduce the rate of persistent post-surgical pain after total knee replacement. This study will randomize 40 patients to receive either CBD dominant or placebo, and follow them for six months to confirm our ability to recruit patients, adhere to protocol, and capture full outcome data for at least 85% of patients.

Study Overview

• Status: Completed
• Conditions: Knee Osteoarthritis
• Intervention / Treatment: Drug: MPL-001 (CBD: THC 25:1); Drug: Placebo oil for oral use

Detailed Description

Approximately 25% of patients develop persistent post-surgical pain (PPSP) after undergoing total knee arthroplasty (TKA), and higher pre-surgery and acute post-operative pain are associated with this outcome. Medicinal cannabis has anti-inflammatory and analgesic properties and may reduce peri-operative pain and the rate of PPSP following TKA. Cannabidiol (CBD) is the active ingredient of interest because of its anti-inflammatory effects and lack of psychoactive effects seen with tetrahydrocannabinol (THC). The primary objective of this pilot trial is to assess the feasibility of a definitive trial to determine the effect of medicinal cannabis, versus placebo, on the proportion of patients experiencing PPSP following TKA. The primary objective of the definitive trial is to determine if medicinal cannabis add-on therapy, versus placebo, reduces the proportion of patients experiencing PPSP at 6 months following TKA. The secondary objectives of the definitive trial are to determine if medicinal cannabis, versus placebo, reduces opioid use, reduces peri-operative pain interference, improves physical functioning, mental functioning, return to function, anxiety and depression, and sleep. The effect of medicinal cannabis, versus placebo, on the incidence of adverse events at 6 months post-surgery will also be examined. In this blinded multi-centre pilot trial, 40 patients will be randomized to receive either oral capsules of CBD oil or visually identical placebo in addition to standard of care pain medications. Participants will be followed for 6 months.

• Study Type: Interventional
• Enrollment (Actual): 39
• Phase: Phase 3

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Hamilton, Ontario, Canada, L8N 4A6
      • St. Joseph's Healthcare Hamilton
    • Toronto, Ontario, Canada, M5B 1W8
      • St. Michael's Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Patients undergoing TKA aged 18 or older
• Cognitive ability and English-language skills required to complete outcome measures
• Provision of informed consent
• Successful completion of the run-in period

Exclusion Criteria:

• Severe cardio-respiratory disease (For operationalizing: ASA 4/NYHA 4)
• Substance use disorder based on DSM-V criteria
• Allergy or intolerance to cannabis, cannabis derivatives, or other ingredients of the study drug
• Patients who are pregnant, planning to be pregnant, or breastfeeding
• Revision TKA
• Bilateral TKA
• Presenting for their pre-surgical consultation less than 4 weeks before surgery
• Patients with a chronic pain condition affecting the knee (other than osteoarthritis) (e.g.: patients with knee pain due to fibromyalgia or chronic pain syndrome will be excluded)
• Unwilling or unable to follow the study protocol

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: MPL-001 (CBD: THC 25:1); 125mg CBD/5 mg THC oil for oral use	Drug: MPL-001 (CBD: THC 25:1); 25:1 cannabidiol (CBD): tetrahydrocannabinol (THC) oral formulation, with a concentration of 50 mg/mL CBD and 2 mg/mL THC, oil- Liquid for oral use
Placebo Comparator: Placebo; Visually identical placebo (medium chain triglyceride oil)	Drug: Placebo oil for oral use; Placebo is Medium-chain triglycerides oil with identical features (in appearance, flavour, and odour) to the MPL-001 oil.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Feasibility - Recruitment Rate (Participants/Month)	Average number of participants enrolled per month. Feasibility predefined as achieving a recruitment rate of ≥6.7 participants/month (equivalent to enrolling 40 participants within 6 months).	From study start to end of recruitment
Feasibility - Proportion of Participants Achieving ≥75% Preoperative Adherence	Proportion of participants who took at least 75% of prescribed study medication doses prior to surgery.	From treatment initiation to surgery, average of 4 weeks
Feasibility - Proportion of Participants Achieving ≥75% Postoperative Adherence	Proportion of participants who took at least 75% of prescribed study medication doses after surgery.	From surgery to 6 weeks post-op
Feasibility - Follow-up Completion	Number of patients completing the 6 month follow-up visit.	6 months post-op

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Persistent Post-surgical Pain (PPSP)	Proportion of patients experiencing moderate to severe PPSP (average of pain over last week of ≥4 out of 10 on a numeric rating scale [NRS])	6 months postop
Time to Opioid Discontinuation	Time from discharge to opioid discontinuation (days).	Up to 6 months post-op
Pain Intensity (Numeric Rating Scale)	Average pain over the past 24 hours measured on a 0-10 numeric rating scale (higher scores indicate worse pain).	Preoperative and 6 months postop
Pain Interference (Numeric Rating Scale)	Pain interference with daily activities measured on a 0-10 numeric rating scale (higher scores indicate greater interference).	Preoperative and 6 months postop
Anxiety and Depression (HADS)	Count of participants with borderline or clinically significant anxiety and depression, assessed using the Hospital Anxiety and Depression Scale (HADS). Scores of 0-7 in each subscale are considered normal, with 8-10 borderline and ≥11 indicating clinically important anxiety or depression.	Preoperative and 6 months post-op
EQ-5D Visual Analogue Scale (VAS)	Health-related quality of life assessed using the EQ-5D instrument. Self-reported overall health measured on a 0-100 scale, where higher scores indicate better health.	Preoperative and 6 months post-op
EuroQol-5 Dimensions (EQ-5D) Index Value	Health utility index derived from EuroQol-5 Dimensions (EQ-5D) responses. Index values typically range from 0 (death) to 1 (full health) but it is also possible to have negative values (worse than death). To calculate index values, we used the Canadian time trade-off (TTO) value set.	Preoperative and 6 months post-op
Insomnia Severity (Insomnia Severity Index)	Proportion of participants meeting criteria for moderate to severe insomnia, assessed using the Insomnia Severity Index (ISI). Standard ISI cutoff scores were used to classify insomnia severity.	Preoperative and 6 months post-op
Return to Function	Return to function assessed as the percentage of preoperative function regained following surgery. Higher percentages indicate greater recovery of function.	Post-op (2 weeks, 6 months)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Feasibility - recruitment	Ability to recruit 40 patients	6 months
Feasibility - retention	Ability to follow 85% of patients	6 months
Feasibility - compliance	Patient compliance with the study treatment (75% of patients comply with 75% of the study doses)	6 months

Collaborators and Investigators

• Sponsor: McMaster University
• Collaborators: St. Joseph's Healthcare Hamilton; Hamilton Health Sciences Corporation
• Investigators: Principal Investigator: Anthony Adili, MD, P.Eng, McMaster University; Principal Investigator: Jason W Busse, DC, PhD, McMaster University

Publications and helpful links

General Publications

• Busse JW, Flood B, Madden K, Ashoorion V, Olaonipekun E, Atrey A, Khanna V, Adili A; Cannabis-TKA Investigators. Cannabidiol to reduce persistent post-surgical pain following total knee arthroplasty: protocol for a multi-centre, randomized, controlled pilot trial. Pilot Feasibility Stud. 2026 Apr 25;12(1):84. doi: 10.1186/s40814-026-01822-w.

Study record dates

Study Major Dates

• Study Start (Actual): May 3, 2023
• Primary Completion (Actual): February 25, 2025
• Study Completion (Actual): February 25, 2025

Study Registration Dates

• First Submitted: January 30, 2019
• First Submitted That Met QC Criteria: January 30, 2019
• First Posted (Actual): February 1, 2019

Study Record Updates

• Last Update Posted (Actual): September 8, 2026
• Last Update Submitted That Met QC Criteria: July 8, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: Total knee arthroplasty; Cannabis; Pilot trial; Persistent post-surgical pain
• Additional Relevant MeSH Terms: Musculoskeletal Diseases; Mental Disorders; Arthritis; Joint Diseases; Rheumatic Diseases; Substance-Related Disorders; Chemically-Induced Disorders; Osteoarthritis; Osteoarthritis, Knee; Marijuana Abuse
• Other Study ID Numbers: Cannabis TKA Pilot Trial

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: We will share IPD upon reasonable request with a data sharing agreement and ethical approval.
• IPD Sharing Time Frame: IPD supporting information will be available upon reasonable request with a data sharing agreement and ethical approval. No time restrictions will apply to data availability.
• IPD Sharing Access Criteria: IPD supporting information will be available upon reasonable request with a data sharing agreement and ethical approval.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No