Pain management continues to be an ongoing challenge in healthcare, and as a somewhat subjective symptom with varying levels of tolerance, it must be individualized. However, prescription pain medications are still being used in epidemic volumes, leading to a continuation of the problem of narcotic tolerance and addiction. In addition, long-term use of non-steroidal anti-inflammatory drugs (NSAIDs) leads to intestinal hyperpermeability and ulceration of the gut. Since the health of the gut is vital for general health and wellbeing, chronic NSAID use is sure to create other health problems with time. In this context, the need for effective alternative or adjuvant pain management therapies is not only optional, but essential.  

The cannabis plant and its therapeutic constituents, cannabinoids, are being well studied for their role in pain management and in fact, pain management is the most common reason for cannabis use. Their effectiveness is rooted in the fact that their biological actions target various pathways related to pain. For example, cannabinoids have been found to exert anti-anxiety, anti-spasmodic, muscle relaxant, anti-inflammatory, and anticonvulsant effects, all of which can be related to chronic pain.

Three main types of pain pathways include nociceptive, neuropathic, and central. Nociceptive pain is caused by damaged body tissue which triggers the immune system to release a host of inflammatory cytokines to the area of damage. Pain is a natural outcome of an activated inflammatory response. Neuropathic pain is caused by damage to sensory or spinal nerves which results in aberrant signals being sent to the brain, such as occurs in diabetic neuropathy. Central pain is caused by central nervous system dysfunction which results in amplification of peripheral signals. Fibromyalgia is an example of central pain.

Cells of injured tissues naturally produce endocannabinoids, anandamide and 2-arachidonoyl-sn-glycerol (2-AG), which activate the cannabinoid receptors to modulate inflammation and dampen the sensations of pain. Understanding the role of endogenous cannabinoids in pain management allows us to better understand the function and place of exogenous cannabinoids in managing more severe pain. Inflammation and nerve injury mobilizes anandamide to modulate nociceptive signals by activating CB1 cannabinoid receptors, while 2-AG responds to acute stress by modulating pain pathways. Both anandamide and 2-AG are first responders to nociceptive signals.

Rather than focusing on local pain signals, exogenous cannabinoids which are dispersed throughout the entire body, offer a more generalized pain modulation. Besides acting on cannabinoid CB1/CB2 receptors, exogenous cannabinoids also interact with G protein-coupled receptor (GPCR) 55 and other well-known GPCRs, such as the opioid or serotonin (5-HT) receptors which are involved in pain modulation. Many of these receptors are located in both peripheral and central neurons which allows for more interaction and crosstalk between various pain pathways.

Inflammatory/Nociceptive Pain

Various animal studies have demonstrated the ability of cannabinoids to effectively suppress inflammation-driven pain. For example, in murine models of rheumatoid arthritis/collagen-induced arthritis, cannabinoids inhibited the production of cytokines, inflammatory cell infiltration and bone destruction associated with arthritis. The outcomes were a reduction in joint swelling, synovial inflammation, and joint destruction. In other animal models of inflammation, including formalin administration to the hind paw of rats, lipopolysaccharide injection into the rat hind paw, and carrageenan-induced inflammation, cannabinoids showed anti-inflammatory and anti-hyperalgesic effects.

Neuropathic Pain

Animal models of neuropathic pain (including chronic nerve constriction traumatic nerve injury, trigeminal neuralgia, chemotherapy- and streptozotocin-induced neuropathy) have also been used to demonstrate the effect of cannabinoids in neuropathic pain management. Neuropathic pain involves upregulation of both CB1 and CB2 receptor expression which activates microglia. When studied on neuropathic pain models, cannabinoid 9-tetrahydrocannabinol (THC) was shown to be highly effective, but had a relatively small therapeutic window before the undesirable psychoactive side effects negated its benefits. Cannabidiol, on the other hand, had a lower efficacy by a wide therapeutic window because of its lack of psychoactive properties. The most effective pain modulating effects were noted in a combination of THC and cannabidiol.

On a broader scope, a systematic review and meta-analysis of cannabinoids for pain management that examined 2454 patients with chronic pain indicated that, compared with placebo, cannabinoids were associated with greater a reduction in pain. The extensive research on cannabinoids, therefore, seems to suggest this group of phytocompounds can offer a safe adjuvant to current pain management therapies in conditions marked by chronic pain.