June 7, 2021
by Hance Clarke, MD PhD; Yuvaraj Kotteeswaran, MD
Cannabis and cannabinoid medicine has been around for centuries. A growing number of countries have created a legal framework within which cannabis and its plant extracts are now legally accessible. Although it would be great to embrace cannabis today as the molecule that might revolutionize medicine and improve the lives of millions of Canadians suffering with headaches, orofacial neuropathic pain, and temporomandibular joint disease, we are not there quite yet – but there is significant potential. Canada created a legislative framework for physicians to authorize medical cannabis in 20131 and followed swiftly with the creation of the Cannabis Act (Bill C-45) which enabled the recreational consumption of cannabis in 20182 after earlier attempts to create a regulated environment guided by physicians seemed futile. Cannabis has also been legislated for recreational use in for adults in 17 U.S. states, while 36 U.S. states have medical cannabis policies.3 Today cannabis products can be found on almost every street corner for access by anyone over the age of 18 years old for recreational purposes. While this has increased access to cannabis products, and increased tax revenues, it has for the time being, also placed science and the ability to study cannabis and cannabinoid medicines on the backburner. Although there is evidence to support the use of cannabis for a variety of health related conditions,4 according to recent research by Health Canada, nearly four million Canadians are self-medicating without a medical document from a healthcare practitioner, meaning they’re turning to the recreational or illicit market rather than going through formal medical channels.5 Canadians interested in a trial of a cannabinoid medicine for conditions such as chronic pain, insomnia, anxiety often get their cannabis related medical information form their neighbours, co-workers or from their local “bud-tender”. This needs to change for the safety of Canadians. Recreational cannabis sales now exceed 250 million dollars monthly from the Canadian public.6
Orofacial Pain Syndromes
Orofacial pain is a chronic pain condition involving the head, face, and/or neck and is associated with dysfunction or primary lesion in the nervous system. The causative mechanisms of many orofacial pain conditions have not yet been fully elucidated but often present with a significant neuropathic pain component without any recognizable lesion to the facial structures. Nerve injury is strongly linked with pain and burning/knife/electric-shock like manifestations. Common disorders causing neuropathic orofacial pain (NOP) include conditions such as burning mouth syndrome (BMS), persistent idiopathic facial pain (PIFP), trigeminal neuralgia (TN) and postherpetic neuralgia (PHN). Unfortunately, the cellular mechanisms underlying these NOPs are poorly understood. Studies have suggested altered dopamine D1 and D2 receptor expression in the putamen of BMS patients7 while Borsani et al8 have recently demonstrated altered expression profiles of the TRPV1 and CB1 and CB2 receptors in human tongue epithelial cells. Various neuropathic mechanisms appear to be operating in PIFP, however alteration in the expression of D2 receptors in the putamen9 and changes in the excitability of primary nociceptive afferents10 contributes to neuropathic pain. Alterations in mu-opioid receptor expression in the nucleus accumbens from PET data suggests that this brain region is linked to TN pathophysiology.11 Ligands of the endocannabinoid system for CB1 and CB2 also can activate TRPV-1 receptors, which detects thermal and nociceptive stimuli.12 Given the co-localization of cannabinoid receptors, TRPV-1 receptors and opioid receptors, there may be considerable “crosstalk” induced by activation of the endocannabinoid system.13
Temporomandibular disorders (TMD) are associated with the impaired function of the temporomandibular joints (TMJ) and the associated neuromuscular system. Osteoarthritis (OA) and Rheumatoid arthritis (RA) are two primary causes of TMD related pain. Studies in animals have shown that cannabinoid receptor activation reduces inflammation and nociceptive processes in skin tissue and joint inflammation models in rodents.14,15 An animal study by Gondim and colleagues found that CB1 and CB2 receptor activation produced anti-inflammatory and antinociceptive effects on arthritis in the temporomandibular joint.16
The Endocannabinoid System and Orofacial Pain
Cannabinoids are chemicals derived naturally from the cannabis plant or are synthetically manufactured. They interact directly with cannabinoid receptors or share chemical similarity with endocannabinoids (or both). Among all of the cannabis constituents, 9-delta-tetrahydrocannabinol (THC) and cannabidiol (CBD) are among the most abundant and well-studied cannabinoids. In addition to THC and CBD, cannabis contains hundreds of phytocannabinoids17 and along with terpenes and flavonoids, the collective interaction of a product on the endocannabinoid system is dependent on its major constituents.18 There has been a tremendous amount of research into the mechanism of action of exogenous THC and CBD and endocannabinoids on the human nervous system, but other phytocannabinoids such as CBG, CBN and others are currently being investigated. Medicinal cannabis contains pharmacologically active cannabinoids that interact with the G protein-coupled endocannabinoid receptors, CB1 and CB2, which serve as binding sites for endogenous as well as exogenous ligands and enzymes synthesizing and degrading those ligands.19
CB1 receptors are expressed throughout the brain and spinal cord in key areas responsible for pain transmission and modulation. CB1 receptors are expressed on neurons throughout the spinothalamic pain pathway including the dorsal root ganglia, the substantia gelatinosa of the spinal cord dorsal horn, ventral posterolateral nucleus of the thalamus, rostral-ventral medulla, and cortex. It is also present in other pain modulatory areas such as the amygdala and peri-aquaductal grey matter.20 The CB1 receptors offer a target for pharmacological intervention for chronic pain. CB2 receptors are expressed on immune tissues and cells such as thymus, tonsils, lymphocytes and macrophages. THC has demonstrated analgesic effects as an agonist at CB1 and CB2 receptors. CBD has been shown to have weak agonist activity at the CB2 receptor and is a negative allosteric inhibitor of the CB1 receptor which has been associated with its ability to reduce the psychotropic effects of THC.21
Numerous preclinical studies have investigated the specific potential of cannabinoids in targeting neuropathic pain and inflammatory pain. In the case of TMD, the osteoarthritic model of pain may give us a glimpse into the potential for cannabis based medicines. Studies suggests that stimulation of CB1 and CB2 receptors alleviates symptoms of osteoarthritis (OA). Various cannabinoid receptors are found in OA cartilage and synovium, including CB1 and CB2, and endocannabinoids are increased in OA synovial fluid compared to normal controls.19 Over the past 5 years in Canada, regardless of the field of medicine, almost any chronic condition that has a component of pain, such as OA (including TMD) , has seen a migration of patients to herbal cannabis products. In humans, one study found that nabiximols (a THC:CBD (1:1) product see below) alleviated symptoms associated with rheumatoid arthritis (RA).22
To date, evidence suggests that cannabis products have potential use in the treatment of chronic neuropathic pain, chemotherapy-induced nausea and vomiting, appetite stimulation and spasticity associated with multiple sclerosis.4 Research into other cannabis related pharmacotherapy treatments for cancer and palliative care, osteoarthritis, and opioid weaning is still ongoing. No randomized controlled clinical trials have taken place to date comparing cannabis products to NSAIDS or placebo. Data investigating the impact of cannabinoids specifically on orofacial pain syndromes in humans continues to be lacking and an arena poised for growth in the years ahead with appropriately randomized controlled trials using validated products.
How does Cannabis Exist today for the Patient?
Cannabinoid drugs currently exist in synthetic THC form as nabilone23 and in a near 1:1 ratio of plant-based THC:CBD extract as a nabixomol marketed as SativexTM.24 More recently, Epidiolex, a CBD liquid, was approved for the treatment of pediatric epilepsy conditions: Lennox-Gastault and Dravet syndromes in the U.S.A and recently the U.K.25 Numerous non-pharmaceutically manufactured and approved cannabis products are also accessible in Canada and all countries in which laws have rendered them legal for sale. The products range from dried plant materials, extracted oil resins from the plant that can be processed into edibles, tablets/capsules, sprays, and topical formulations (i.e. gels, creams). These products contain multiple cannabinoids.
We cannot use data from Nabiximols (purified 1:1 CBD:THC plant extract) and nabilone (a synthetic cannabinoid derivative that mimics THC) exclusively for clinical guidance because they are different to the plant based extracts commonly being consumed by the public or currently being authorized by physicians. A PubMed search will reveal hundreds of reviews examining various therapeutic uses for cannabis over the past 5-10 years. Most concluded that there is an absence of, or only weak evidence to support the use of cannabis for the clinical indication studied. Without randomized controlled trial data, evidence for plant-based formulations (dried plant products, plant-based oil extracts, topical formulations etc.), guidelines will continue to suggest that there is a lack of evidence26 because none can exist until the regulatory frame- work changes in North America and clinician scientists can pursue the needed trials with a Health Canada approved product. The authorizing physician must always ensure that the known risks (in particular with THC products) such as hallucinations, psychosis and cardiovascular events (ie, tachycardia and vasodilation) are weighed against the possible benefits.
There continues to be a stigma around cannabis/cannabinoid medicines which synonymizes it’s use as consuming “weed” or a “joint”. Given the rapid evolution of the cannabis industry and the appetite of different demographics (middle aged / elderly Canadians) to gravitate to a trial of cannabis based medicines, this viewpoint needs to shift. There exists multiple dosage forms as eluded to earlier not simply “joints”. Furthermore, oil-based cannabis products (ie, oil extracts and capsules) authorized for a medical condition often begin with doses as low as 5-20 mg (CBD) and 1-3 mg (THC). At these low doses, these products are unlikely to produce negative/unwanted side effects and are titrated to effect similar to many other medications used in pain medicine. At these lower doses, there is a significantly lower effect at the cannabinoid receptors compared to consuming inhaled high dose THC products where the dose can be in the 100s of milligrams per consumption. Criticisms regarding the regulatory framework supporting the cannabis industry continue, and the ability of the major cannabis producers to produce a reliable and consistent product remains a concern. Given that none of these substances are regulated similar to other prescribed drugs (with the exception of Epidiolex), there can be significant batch-to-batch variation.
In a recent study, we found that 1 in 5 patients presenting for surgery due to an osteoarthritic condition were consuming a cannabis product.27 Only 25% of the patients understood the cannabinoid constituents in the cannabis product they were consuming. One third were being authorized from a Health Canada licensed producer. In order for us to integrate these procducts into a patients regimen we must also have reassurance regarding the type of product and the amount of the specific cannabinoid (i.e. CBD and/or THC) being consumed by the patient in order to appropriately care for them.28
Current national study
In an attempt to bring standardization to the cannabinoid medicine environment and move the science related to cannabis use forward, the Medical Cannabis Real World Evidence (MCRWE) was launched in 2020. The MCRWE is a national, first of its kind study, that has the ability to enroll patients from coast to coast.29 The aim of this research study is to understand the effects of medical cannabis over a 6 month time period in adult patients with chronic pain, sleep, anxiety or depression. All strains must be authorized by a physician and have the phytocannabinoid profiles documented and patients are tracked using validated and standardized questionnaires which focus on pain, sleep, anxiety depression and quality of life. The study will enroll 2,000 patients. Any physician interested in learning more about the ongoing study can visit https://www.mcrwe.ca/. The study has research ethics board approval. A common limitation for access to cannabis by patients is the unwillingness of many health care practitioners to authorize most often due to a lack of knowledge. If a health care practitioner is interested in learning more about the basics of cannabis authorization and would like to understand the risks/benefits of cannabinoid medicine before their initial authorization document, where might credible resources be found to fill the knowledge gap?
Where can credible cannabis education be found?
Finding a physician/dentist/nurse practitioner that is knowledgeable and can guide a patient to safely integrate cannabis based medicines into their medical regimen can be a challenge as alluded to at the outset. For many health care practitioners interested in learning more about the science of cannabis and cannabinoid medicine a new Canadian resource was recently launched. The Canadian Consortium for the Investigation of Cannabinoids (CCIC) in the spring of 2021 has launched the Canadian Cannabis Syllabus (CCS). This University of Calgary accredited continuing medical education program has 9 modules and can be accessed at ccic-learncannabis.ca, it presents the science of the endocannabinoid system, discusses the safety and efficacy of cannabis/cannabinoids as therapeutic agents and provides an approach to discussing cannabinoids as a treatment option in patient care. Without evidence based-information, physicians will have a hard time discussing cannabis based medicines with their patients.
An observational study by our group, found that one-third of chronic pain patients remained on medical cannabis for six months after the initiation of a cannabis product. Patients that were able to find a product that worked for them reported that their pain intensity and pain interference scores were reduced and quality of life and general health symptoms scores were improved.30 Orofacial Pain continues to be a condition resistant to many conventional treatments. Today’s patients continue to seek alternative treatment options in hopes of funding a good adjunct to their current medication regimen. Given the early evidence in osteoarthritis and the documented analgesic properties of several cannabinoids, the careful introduction of a cannabis based medicine for orofacial pain can be entertained providing the health care professional also entertains a risk – benefit discussion with his or her patient. Until our federal government enables us to have products that we can test in randomized controlled interventions (to date no plant extract has been approved for use in an RCT), the science will severely lag behind as the population continues to self medicate with this drug. Real world data such as that being collected within the MCRWE study is essential and we must understand outcomes which are evaluated based on the phytocannabinoids being consumed from the products in today’s marketplace. This for now, is our best opportunity to move science forward for the Canadian population and better understand the longterm potential for cannabis in the treatment of conditions such as orofacial pain.
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About the Authors
Yuvaraj Kotteeswaran is a Staff Anesthesiologist and Interventional Pain Physician in the Department of Anesthesia at Thunder Bay Regional Health Sciences Centre. Completed Fellowship in Chronic Pain at University of Toronto under the mentorship of Dr. Hance Clarke, specializes in Regional Anesthesia, Transitional Pain and Chronic Pain Management. He is associated with the Northern Ontario School of Medicine, Thunder Bay, Ont.
Dr. Clarke is the Director of Pain Services and the Pain Research Unit at the Toronto General Hospital (TGH). He is the Knowledge Translation Chair for the University of Toronto Centre For the Study of Pain and also an Associate Professor in the Department of Anesthesiology and Pain Medicine at U of T.