Clinical trial NCT06448923: Cannabidiol After Multi-Trauma for Pain and Opioid Therapy
Official title: Effects of an Acute 1-month Cannabidiol Treatment on Pain and Inflammation After a Long Bone Fracture: a Triple-blind Randomized, Placebo Controlled Clinical Trial
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: PHASE2
Conditions: Fracture
Keywords: Cannabidiol
Trauma
Pain
Inflammation
Fracture
Orthopaedic
Lead sponsor: Centre Integre Universitaire de Sante et Services Sociaux du Nord de l'ile de Montreal
Sponsor class: OTHER
First posted: 2024-06-07
Enrollment: 168
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The aim of this project is to investigate the therapeutic potential and safety of acute Cannabidiol (CBD) treatment on longitudinal pain symptoms, and to assess potential interactions with pain mediators including opioids and sex on CBD treatment response. To this end, this research protocol proposes a comprehensive translational approach including a placebo-controlled randomized clinical trial comparing two daily doses of CBD treatment administered for one month on pain relief. This study will also compare intervention conditions on inflammation markers, participant quality of life, sleep quality, depression, anxiety, cognition and orthopaedic function.

Detailed description: The level of pain in the acute phase after injury is a predictor of the development of chronic pain. Chronic pain is defined as pain that persists for more than 3 months post-accident and impairs functional recovery. Mechanistically, it has been shown that acute nonspecific inflammation triggered after peripheral injury results in the continuous release of proinflammatory cytokines that weaken the blood-brain barrier, facilitating the entry of toxins that can invade the central nervous system (CNS). The resulting sustained inflammation of the CNS plays an important role in establishing the maladaptive plasticity process underlying pain chronification. Cannabidiol (CBD), a component of cannabis devoid of addictive or psychotropic effects, stands out as a potential therapeutic agent given its analgesic and anti-inflammatory properties as well as its potential to enhance the biomechanical properties of bone healing. Given the excellent safety profile of CBD and its inhibitory effects on microglial activity, the primary mechanism of neuroinflammation and pain, CBD has the potential to promote acute pain relief while reducing reliance on addictive opioid treatments, hence facilitating recovery in trauma patients.

This study is a randomized, placebo controlled, human pilot clinical trial evaluating the effects of two doses (low and moderate) of CBD vs. placebo on pain after orthopaedic trauma.

Risks of adverse effects are considered low given the demonstrated excellent safety profile of CBD. CBD was also shown to accentuate opioid analgesic effects, thus reducing required opioid doses for patient comfort. The most likely adverse events associated with CBD in adult patients include somnolence, fatigue, drowsiness and decreased appetite. Access to on-duty emergency physicians at the recruiting site will be provided during the entire treatment duration.

A 30 percent relative pain intensity reduction on the Visual Analog Scale (VAS) (expected response of 50 percent or more in the CBD group and expected 20 percent in the placebo group) has been used extensively to reflect clinically significant pain relief in clinical trials. Based on a Fisher's exact test, a sample size of 168 participants (3 groups of 56) will be required to reach a power of 80 percent to detect a statistically significant difference in the proportion of patients who reaches 30 percent pain reduction between the CBD groups and placebo at 1-month post-injury, assuming a dropout rate of 20 percent and a significance level of 5 percent. These parameters are taken from a successful randomised, placebo-controlled clinical trial using Sativex© in treating 125 neuropathic pain patients.

Our group has ensured the feasibility of conducting such a pilot clinical trial in multi-trauma patients with the recruitment of 110 patients in less than 18 months to take part in a 10-session, outpatient treatment trial. A partnership with Canadian company EmpowerPharm will enable the use of pharmaceutical-grade synthetic CBD samples and identical placebos. The pharmacokinetic profile of the CBD product has been established.

Eligibility criteria: Inclusion Criteria:

* Patients admitted to the Hopital du Sacre-Coeur de Montreal (HSCM), within 7 days of the accident for a long bone fracture with or without mTBI
* Subject has provided informed consent
* Subject is between 18 and 70 years old

Exclusion Criteria:

* Moderate/severe traumatic brain injury (TBI)
* Diagnosis of any of the following mental disorders as defined by the DSM-5: schizophrenia, intellectual deficiency, bipolar disorder, major depression, undiagnosed and untreated sleep disorders
* History of alcohol or opioid misuse/abuse
* Evidence of severe renal (stage 4 or 5) or hepatic impairment (stage B or C)
* Pregnant or lactating women, women of childbearing potential who are not using medically accepted forms of contraception, or women who are planning on becoming pregnant
* History of adverse reactions to cannabis
* Patients taking warfarin, sildenafil, valproate or under opioids treatment prior to the injury
* Patients experiencing on average mild-to-absent pain in the last 24h preceding recruitment (as per a score \<30 on a 0-100mm Visual Analogue Scale (VAS))
* Transport business drivers and heavy machinery operators
* A diagnosis of chronic pain, bone pathology (osteoporosis) or chronic inflammatory disease (rheumatoid arthritis, arthritis, psoriasis)
* Not have French or English as a spoken language
* A weighted MoCA score of less than 24
* Regular cannabis use of more than 5 times a week

Primary outcomes:
measure: Change From Baseline on Pain Intensity Rating on a Visual Analog Scale (VAS) at Week 4
timeFrame: Baseline and 4 weeks
Secondary outcomes:
measure: Response Rate - 50 Percent or Greater Reduction in Pain Intensity on a Visual Analog Scale (VAS)
timeFrame: 4 weeks
measure: Change in Pain Rating on the Brief Pain Inventory Short Form (BPI-sf) Between Interventions
timeFrame: 4 weeks and 3 months
measure: Change in Blood Level Inflammation Over Time and Between Interventions
timeFrame: Baseline, 4 weeks and 3 months
measure: Opioid Usage Monitoring
timeFrame: Ongoing from baseline to 3 months
measure: Change in the Orthopaedic Function Using The Short Musculoskeletal Function Assessment (SMFA) Questionnaire Between Interventions
timeFrame: 4 weeks and 3 months
measure: Change in Quality of Life Using the Short Form (36) Health Survey Between Interventions
timeFrame: 4 weeks and 3 months
measure: Change in Sleep Quality Using the Pittsburgh Sleep Quality Index (PSQI) Between Interventions
timeFrame: 4 weeks and 3 months
measure: Change in Depression Symptoms Assessment Using the Beck's Depression Inventory-II Between Interventions
timeFrame: Baseline, 4 weeks and 3 months
measure: Change in Anxiety Symptoms Assessment Using the Beck's Anxiety Inventory Between Interventions
timeFrame: Baseline, 4 weeks and 3 months
measure: Change in Speed of Information Processing using Symbol Search from the WAIS-IV Battery Between Intervention
timeFrame: Baseline, 4 weeks and 3 months
measure: Change in Attention using Elevator counting with distraction from the Test of Everyday Attention Battery Between Intervention
timeFrame: Baseline, 4 weeks and 3 months
measure: Change in Attention using Elevator counting from the Test of Everyday Attention Battery Between Intervention
timeFrame: Baseline, 4 weeks and 3 months
measure: Change in Memory using the California Verbal Learning Test Between Interventions
timeFrame: Baseline, 4 weeks and 3 months
measure: Change in Memory using Digit Span from the WAIS-IV Battery Between Intervention
timeFrame: Baseline, 4 weeks and 3 months
measure: Change in Executive Fonction using the D-KEFS Color-Word Between Interventions
timeFrame: Baseline, 4 weeks and 3 months
measure: Change in Executive Function using the D-KEFS Verbal Fluency Between Interventions
timeFrame: Baseline, 4 weeks and 3 months
Other outcomes:
measure: Pain catastrophization using the Pain Catastrophizing Scale
timeFrame: Baseline
measure: Change in mTBI symptoms resolution using the Rivermead Post-Concussion Questionnaire (RPQ)
timeFrame: Baseline, 4 weeks and 3 months
measure: Treatment Expectation using the Treatment Expectation Questionnaire (TEX-Q-F)
timeFrame: Baseline
measure: Symptoms of Post-Traumatic Stress Disorder using the PTSD Checklist for DSM-5 (PCL-5) questionnaire
timeFrame: Baseline and 4 weeks
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