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: Recruiting
• 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 (Estimated): 40
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Anthony Adili, MD, P.Eng; Phone Number: 36062 (905) 522-1155; Email: adilia@mcmaster.ca
• Study Contact Backup: Name: Kim Madden, PhD; Phone Number: (289) 237-7380; Email: maddenk@mcmaster.ca

Study Locations

• Canada
  • Ontario
    • Hamilton, Ontario, Canada, L8N 4A6
      • Recruiting
      • St. Joseph's Healthcare Hamilton
      • Contact: Anthony Adili, MD, P.Eng; Phone Number: 36062 (905) 522-1155; Email: adilia@mcmaster.ca
    • Toronto, Ontario, Canada, M5B 1W8
      • Not yet recruiting
      • St. Michael's Hospital
      • Contact: Amit Atrey, MD; Phone Number: 1(416)864-5342; Email: amit.atrey@unityhealth.to

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
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

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Opioid use	Use of opioids (mean morphine equivalent dose [MED] change)	6 months
Peri-operative pain intensity	Peri-operative pain measured on an 11-point NRS	24-48 hours, 2-weeks, 6-weeks, 3-months and 6-months
Pain interference	Pain interference measured by the Brief Pain Inventory (BPI-SF)	24-48 hours, 2-weeks, 6-weeks, 3-months and 6-months
Physical function	Physical component summary (PCS) score of the SF-12	6 months
Mental function	Mental component summary (MCS) score of the SF-12	6 months
Return to function	Return to 80% of pre-injury function (work, leisure, home activities)	6 months
Insomnia	Insomnia symptoms on the Insomnia Severity Index (ISI)	6 months
Anxiety and depression	Anxiety and depression on the Hospital Anxiety and Depression Scale (HADS)	6 months
Safety - Adverse events	Serious and non-serious adverse events	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; Principal Investigator: Vahid Ashoorion, MD, PhD, McMaster University

Study record dates

Study Major Dates

• Study Start (Actual): May 3, 2023
• Primary Completion (Estimated): August 1, 2024
• Study Completion (Estimated): August 1, 2024

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): July 3, 2023
• Last Update Submitted That Met QC Criteria: June 29, 2023
• Last Verified: June 1, 2023

More Information

Terms related to this study

• Keywords: Total knee arthroplasty; Cannabis; Pilot trial; Persistent post-surgical pain
• Additional Relevant MeSH Terms: Pathologic Processes; Postoperative Complications; Pain; Neurologic Manifestations; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Arthritis; Osteoarthritis; Pain, Postoperative; Osteoarthritis, Knee
• Other Study ID Numbers: Cannabis TKA Pilot Trial

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

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