Phytocannabinoids in Combination: Chronic Pain

Background: Chronic pain, one of the most common reasons adults seek medical care, has been linked to restrictions in mobility and daily activities, dependence on opioids, anxiety, depression, sleep deprivation, and an overall reduced quality of life. Unfortunately, the current treatment options for chronic pain are limited, often ineffective, and have associated side effects. Better outcomes can be achieved by developing new and improved therapeutics or more immediately by identifying favorable drugs that are already available or emerging as potential new analgesics. There is a growing interest in the use of opioid-sparing analgesics, in particular medicinal cannabis, for pain management. It has also been suggested that compounds in the cannabis plant function more efficiently in concert with each other rather than alone - a concept known as the “entourage effect.” This study aims to test the safety and efficacy of chronic separate and combined administration of Beta-Caryophyllene (BCP) and cannabidiol (CBD), two constituents of the cannabis plant, in mitigating chronic inflammatory pain. Safety profiles of these substances, both isolated and in concert, were also examined. Methods: In mice, we used a chronic inflammatory pain model (Complete Freund's Adjuvant, CFA) and two pain-like behavioral tests. Mechanical allodynia was tested using the digital Von Frey method, where a filament is applied with increasing force to the hind paw to obtain a paw withdrawal threshold. Cold allodynia was assessed via acetone applied to the plantar surface of the hind paw; time spent lifting, licking, and shaking the stimulated paw was recorded. We determined the analgesic effects of daily injections of the combination of CBD and BCP and monitored for adverse effects. Results: We found that daily injection of the combination of CBD and BCP in this chronic inflammatory pain model maintained its analgesic effect and functioned synergistically in reducing mechanical and thermal hypersensitivity. No adverse effects on body weight, body temperature, locomotion, or liver toxicity were noted. Conclusion: The present data show that the combination of BCP and CBD maintains its analgesic effect with safety profiles in a chronic pain state. This suggests that this combination can serve as alternative analgesic therapy for chronic pain and support the entourage effect of cannabinoids.