Improving Pain Disability With the Use of Oral Cannabinoids

Study Overview
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Brief Summary
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The investigators are conducting a pilot (i.e. a small study) in order to find out the effectiveness and safety of medical cannabis in the management of chronic pain. At the end of this 3 month study, investigators will gather information on how easy it is for patients to enroll and complete the entire study. The results of this pilot study will help the study team design a larger randomized controlled trial.

Detailed Description
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Chronic pain is defined as pain lasting longer than three months, affects  20% of Canadian adults. In addition to having a significant negative impact at the individual patient level (i.e., decreased quality of life and functioning), chronic pain is also a main cause of disability and health care use. Opioids are frequently prescribed to manage chronic pain despite limited data on their long term usefulness and has become one of the major contributors to the current opioid crisis in Canada. Chronic pain can potentially be treated with medical cannabis as an adjunct or alternative to opioids due to their similar behavioral, anatomical and biochemical mechanisms. Cannabinoids also potentially prevent the development of tolerance to opioids when co-administered. Cannabinoids have demonstrated the ability to reduce pain as well as opioid-sparing effects in pre-clinical and clinical studies however further research is needed to identify the optimal make-up, ratio, and dosage of cannabinoids to minimize harms and maximize benefits. Furthermore, studies conducted to date have methodological problems such as short follow-up windows (hours or days) that limit conclusions. The investigators therefore propose a randomized, placebo-controlled trial of oral cannabinoids [CBD (cannabidiol) alone or in combination with THC (delta-9-tetrahydrocannabinol)] for reducing pain disability and opioid use for pain management in chronic pain. However, there are a number of feasibility issues that should be addressed prior to launching a full-scale trial in this area. Some issues have been identified in the literature (e.g., success of blinding) while others are related to the changing socio-medico-legal landscape surrounding cannabis use in Canada. The purpose of this pilot study is to test the study plan, patient recruitment and compliance with the study procedures. Results of this study may be used as a guide for larger studies and will help us determine if medical cannabis can reduce daily opioid doses and/or decrease pain interference (disability) in chronic pain patients. This study will aim to recruit 51 patients from the Toronto General Hospital Transitional Pain Service. Study Procedure: After obtaining the Informed consent, patients will be randomized into one of the three study groups. Patients will either receive CBD oil, CBD+THC oil or placebo orally for 12 weeks. Starting dose will be 1 ml per day. The dose of study drug will be adjusted based on patients' reported efficacy and adverse effects. After starting the study drug, patients will have scheduled study visits either remotely or in-person at 4, 8, and 12 weeks plus a follow up calls or virtual clinic visit(OTN) at 2 and 6 weeks. At every study visit, patients will be asked to complete the questionnaires that will assess their pain level and how it affects their quality of life, opioid use, and side effects if they are experiencing. The investigators will also collect information on: demographic and baseline characteristics (e.g., sex, age, height, weight, and body mass index) and medical history (including prior and concomitant medications) via patient interview or from inspection of medical records. Additionally, symptoms of depression and anxiety will be measured with the validated screening tools at baseline and 12 weeks post-treatment.

Official Title
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A Single-centre, Pilot, Randomized Controlled Trial of Oral Cannabinoids for Improving Pain Disability in Patients With Chronic Pain

Conditions
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Chronic Pain, Opioid Use, Cannabis

Intervention / Treatment
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* Drug: CBD oil ( MPL-001)
* Drug: CDB+THC oil (MPL-005)
* Drug: Placebo oil


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥ 25 years Able to understand and read English Experiencing chronic, non-palliative pain Exclusion Criteria: Use of nabilone, nabiximols or cannabis in the 30 days preceding study recruitment Known allergy to cannabis or any cannabinoid Serious ongoing medical issues (i.e., lung, liver, kidney or heart disease) that in the opinion of the Investigator would compromise the safety of the patient Current uncontrolled serious mental disorders such as schizophrenia, or psychosis Currently pregnant or breast-feeding (a negative urine pregnancy test must be obtained for women of child bearing potential during pretreatment evaluation) Men and women planning to start a family in the next 12 weeks Has declared a current alcohol or substance use disorder (excluding opioid use disorder) Currently using Methadone or Buprenorphine Patients who are naïve to pain treatments

Ages Eligible for Study
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Minimum Age: 25 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
Interventional Model Description: Participants will be randomized to receive either a placebo, CBD oil (medical cannabis) or CBD+THC oil (medical cannabis) in a 1:1:1 ratio.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CBD oil<br>Participants will receive CBD (cannabidiol) oil for a total duration of 12 weeks. | Drug: CBD oil ( MPL-001)<br>* MPL-001: which is a 25:1 Cannabidiol (CBD): ∆9-tetrahydrocannabidiol (THC) oral formulation with a concentration of 50 mg/ml of CBD and 2 mg/ml of THC. The starting dose will be 1 mL per day (50 mg CBD) orally and gradually titrated to a maximum dose of 6 mL (300 mg CBD) per day in a divided dosage within 6 to 8 weeks of treatment initiation based on patient assessment. Once the optimal dose has been determined, which maximizes potential therapeutic effects while minimizing adverse effects, the dose will be maintained for the remainder of the trial.<br>* Other names: CBD concentrate;|
| Experimental: CBD+THC oil<br>Participants will receive CBD (cannabidiol) oil in combination with THC (delta-9-tetrahydrocannabinol) for a total duration of 12 weeks. | Drug: CDB+THC oil (MPL-005)<br>* MPL-005: which is a 5:1 Cannabidiol (CBD):∆9-tetrahydrocannabidiol (THC) oral formulation with a concentration of 25 mg/ml of CBD and 5 mg/ml of THC. The starting dose will be 1 mL per day (25 mg CBD + 5 mg THC) orally and gradually titrated to a maximum dose of 6 mL (150 mg CBD + 30 mg THC) per day in a divided dosage within 6 to 8 weeks of treatment initiation based on patient assessment. Once the optimal dose has been determined, which maximizes potential therapeutic effects while minimizing adverse effects, the dose will be maintained for the remainder of the trial.<br>* Other names: CBD concentrate;|
| Placebo Comparator: Placebo oil<br>Participants will receive matching placebo oil for a total duration of 12 weeks. | Drug: Placebo oil<br>* The starting dose will be 1 mL per day (contains no API) orally and gradually titrated to a maximum dose of 6 mL per day in a divided dosage within 6 to 8 weeks of treatment initiation based on patient assessment. Once the optimal dose has been determined, which maximizes potential therapeutic effects while minimizing adverse effects, the dose will be maintained for the remainder of the trial.<br>* Other names: Matching placebo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Feasibility outcome: pertaining to the patients recruitment | The ability to recruit the necessary number of patients during the estimated 12-month period | Through study completion, an average of 1 year | 
| Feasibility outcome: pertaining to adherence to intervention | Defined as ≥70% of patients taking ≥70% of the prescribed doses and assessed from the participant-kept study drug diary data at each study visit. | Up to 12 weeks post-treatment | 
| Feasibility outcome: pertaining to withdrawal from study | Participant withdrawal from the study <20% | Up to 12 weeks post-treatment | 
| Feasibility outcome: pertaining to questionnaire data | The amount of missing data from all questionnaires <20% | Up to 12 weeks post-treatment | 
| Feasibility outcome: the rate of unintentional unblinding | Defined as the participant correctly identifying group allocation and blinding success will be quantified using the BANG Index. | Up to 12 weeks post-treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The mean Morphine Equivalent (MEQ) dose (mg/day) at 12 weeks post-treatment for patients that were consuming opioids at the start of the trial | The data for opioid consumption will be extracted from the medical record or obtained via self report. MEQ will be calculated based on the 2017 Canadian Guideline for Safe and Effective Use of Opioids for Chronic Non-Cancer Pain. | Baseline and at 2-,4-,6-,8- and 12-weeks post-treatment | 
| The mean pain interference at 12 weeks post-treatment | Pain interference will be assessed with The Patient Reported Outcomes Measurement Information System (PROMIS) Pain Interference - Short Form 8a scale. This validated scale consists of 8 items detailing the extent to which pain interferes with the individual's abilities to perform and enjoy daily life; each item is rated on a 5-point scale (1=not at all, 2=a little bit, 3=somewhat, 4=quite a bit and 5=very much). Scores are calculated from the total of item responses, with higher scores reflecting greater pain interference. | Baseline and at 2-,4-,6-,8- and 12-weeks post-treatment |