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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Knee Osteoarthritis

Intervention / Treatment
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* Drug: MPL-001 (CBD: THC 25:1)
* Drug: Placebo oil for oral use


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: MPL-001 (CBD: THC 25:1)<br>125mg CBD/5 mg THC oil for oral use | Drug: MPL-001 (CBD: THC 25:1)<br>* 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<br>|
| Placebo Comparator: Placebo<br>Visually identical placebo (medium chain triglyceride oil) | Drug: Placebo oil for oral use<br>* Placebo is Medium-chain triglycerides oil with identical features (in appearance, flavour, and odour) to the MPL-001 oil.<br>|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Total knee arthroplasty, Cannabis, Pilot trial, Persistent post-surgical pain