Cannabidiol and Cannabigerol, Nonpsychotropic Cannabinoids, as Analgesics that Effectively Manage Bone Fracture Pain and Promote Healing in Mice

Abstract

Bone fractures are among the most prevalent musculoskeletal injuries, and pain management is an essential part of fracture treatment. Fractures heal through an early inflammatory phase, followed by repair and remodelling. Nonsteroidal anti‐inflammatory drugs (NSAIDs) are not recommended for fracture pain control as they potently inhibit the inflammatory phase and, thus, impair the healing. Opioids do not provide a better alternative for several reasons, including abuse potential. Accordingly, there is an unmet clinical need for analgesics that effectively ameliorate post‐fracture pain without impeding the healing. Here, we investigated the analgesic efficacy of two non‐psychotropic cannabinoids, cannabidiol (CBD) and cannabigerol (CBG), in a mouse model for tibial fracture. Mice with fractured tibiae exhibited increased sensitivity to mechanical, cold, and hot stimuli. Both CBD and CBG normalized pain sensitivity to all tested stimuli, and their analgesic effects were comparable to those of the NSAIDs. Interestingly, CBD and CBG promoted bone healing via multiple mechanisms during the early and late phases. During the early inflammatory phase, both cannabinoids increased the abundance of periosteal bone progenitors in the healing hematoma and promoted the osteogenic commitment of these progenitors. During the later phases of healing, CBD and CBG accelerated the fibrocartilaginous callus mineralization and enhanced the viability and proliferation of bone and bone‐marrow cells. These effects culminated in higher bone volume fraction, higher bone mineral density, and improved mechanical quality of the newly formed bone. Together, our data suggest CBD and CBG as therapeutic agents that can replace NSAIDs in managing post‐fracture pain as both cannabinoids exert potent analgesic effects and, at the same time, promote bone healing.This article is protected by copyright. All rights reserved.

Role of Resolvins in Inflammatory and Neuropathic Pain

“…Among the various components of cannabis, reports note that cannabidiol and tetrahydrocannabinol are mainly involved in various bioactivities by interacting with various orphan G protein-coupled receptors (GPCRs) and nuclear factors or regulating several ionotropic receptors, transporters, and enzyme activity [27,28]. In addition, until recently, research to improve the efficiency of cannabidiol, which shows irregular or low-efficiency effects, has also been reported [29][30][31]. Widely known drugs such as opioids and morphine are also phytoconstituents obtained from Papaver somniferum (opium poppy) [32,33], and the bioactivities and mechanisms of various phytoconstituents are being studied.…”

Therapeutic Potential of Cannabidiol and Cannabigerol in Fracture Healing

“…I n this issue of JBMR, Khajuria and colleagues [1] report an important translational study on the potential therapeutic effect of two phytocannabinoids, cannabidiol (CBD) and cannabigerol (CBG), in a mouse model of fracture healing. The main outcomes of this study are that both compounds alleviated pain at levels similar to nonsteroidal anti-inflammatory drugs (NSAIDs) and opiates and stimulated bone healing by increasing the callus mineral density and bone volume fraction (BV/TV) and by improving the biomechanical properties.…”