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

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% relative pain intensity reduction on the VAS (expected response of 50% or more in the CBD group and expected 20% 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 225 participants (3 groups of 75) will be required to reach a power of 80% to detect a statistically significant difference in the proportion of patients who reaches 30% pain reduction between the CBD groups and placebo at 1-month post-injury, assuming a dropout rate of 20% and a significance level of 5%. These parameters are taken from a successful randomised, placebo-controlled clinical trial using Sativex© in treating 125 neuropathic pain patients. Moreover, considering that the placebo group may ingest more opiates and that the anticipated inter-group effect at one month may be reduced to 20%, a total sample size of 225 subjects could be required to achieve 80% power, assuming a drop-out rate of 20% and a significance level of 5%.

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.