Cannabinoids are the chemical constituents of the Cannabis plant. There are three general categories of cannabinoids present, including phytocannabinoids, endocannabinoids, and synthetic cannabinoids. Phytocannabinoids are cannabinoids found in the plant and are structurally related to delta-9-tetrahydrocannabinol (THC). Endocannabinoids are found in human and animal tissue and exert effects typically on the nervous and immune system. Synthetic cannabinoids are commercially produced substances that attach to cannabinoid receptors and exert an effect on the body. The highest concentration of phytocannabinoids is found in flowers of the Cannabis plant but leaves and stems are also used to produce medicinal products, such as edibles, oils, tinctures, resins, and plant extracts ( Table 11.1 ).
|Form||Other Terms||Development||Route of Administration|
|Plant||Flower, bud||The highest concentration of cannabinoids is found in the flower, not the lead, of the female plant; topical preparation and rectal suppositories can be made with dried flower or plant extract||Smoking |
|Edibles||Brownies, cookies, candy||Typically butter or oil used to extract cannabinoids and put into a variety of edible products||Oral|
|Tincture||Golden dragon |
|Alcohol or glycerin used to extract active ingredients||Oral |
|Alcohol use to make highly viscous concentrated extract||Oral |
|Resin||Hash, dry sift, kief||Concentrate made by mechanically separating trichomes (hair-like protrusion on flower with high concentration of cannabinoids) from the plant||Oral mucosal|
|Nabiximols||Sativex TM||Pharmaceutically prepared whole plant extract in spray form; 1:1 THC:CBD concentration; approved for prescription use in many countries outside of United States||Oromucosal|
|Dab||Wax, shatter||Ultraconcentrated extract made with solvents such as butane; very high levels of THC; risk of overdose and acute psychosis||Dabbing (concentrate placed on very hot metal rod and inhaled)|
|Pharmaceutical cannabinoids||Dronabinol TM |
|Dronabinol TM and Nabilone TM are FDA-approved synthetic THC (used for chemotherapy-induced nausea, vomiting; AIDS-related cachexia); Epidiolex TM is a highly purified CBD plant extract and is FDA approved for the treatment of two rare epilepsy syndromes||Oral|
Depending on the form of Cannabis product used, the route of administration changes from oral to smoking, vaporization, and topical applications. Although smoking and vaporization produce rapid drug onset and peak levels, vaporization results in a substantially higher blood concentration level of THC. This may lead to increased adverse effects in novice users compared with smoking. Cannabis can also be added to foods such as brownies, cookies, and other common items commonly referred to as edibles. Ingesting edibles results in a slower drug onset and longer duration of action, making dose titration difficult. After ingestion, THC is metabolized to 11-OH-Δ9-tetrahydrocannabinol (11-OH-THC), a more potent psychoactive form. The presence of 11-OH-THC metabolites increases the risk of overdose in novice users ( Table 11.2 ).
|Notes||Combustion of dried cannabis flower using several methods: cigarettes (joints, spliffs), pipes, water pipes (bongs)||Vaporizer is used to heat dried flower or concentrated extract (oil, resin) and the resultant vapor is inhaled||Variety of edibles is available; often dose/single serving is a fraction of the product (i.e., one part of a cookie or brownie)||Many forms are available: creams, ointments, patches, poultices, oils|
|Pharmacology||Rapid onset and peak||Rapid onset and peak similar to smoking||No inhalation; broad range of products; slower onset and longer duration of action||None of the pulmonary effects associated with inhalation; probably much less intoxicating|
|Cautions||Bronchial irritation; cough, sputum; production contains carcinogens; potential for adverse effects on lungs function with heavy use over many years||Substantially higher blood THC concentrations achieved at a given dose than with smoking; higher risk of adverse effects in novice users; long-term lung safety is unknown; need for potentially costly equipment; potentially fatal vaping-related pulmonary illness||Onset and peak are delayed, and effects can last many hours which make it more difficult to titrate dose; oral metabolite of THC (11-OH-THC) may have fourfold more powerful psychoactive effect; risk of overdose; caution especially in novice users||Very little is known about topical preparations; unknown systemic absorption|
Cannabinoid and Opioid Receptors: The Evidence
In this chapter, cannabis and marijuana will be used interchangeably. There is scientific evidence as to how and why cannabinoids may be potentially useful in pain. It is also important to note there are different neurobiological mechanisms in acute and chronic pain. Pain, generically, is a broad diagnosis and there are many different types of pain. Generally speaking, there are somatic, visceral, neuropathic, and psychogenic pain disorders and pain of different origins may respond differently to different types of medications. Under each of those generic types of pain, there may be several other subtypes of pain. For example, neuropathic pain may be due to an organic cause, such as diabetes mellitus, or may be related to underlying central nervous system trauma or disease, such as spinal cord injury. Visceral pain may be related to gastrointestinal disease or space occupying lesions. The management of each of these conditions will likely be different, with some potential overlap.
The two most studied cannabinoids used for medicinal purposes are THC and cannabidiol (CBD) depicted in Fig. 11.1 . Both THC and CBD have the same molecular formula (C₂₁H₃₀O₂) and interact with cannabinoid receptors. However, they have different molecular configurations, receptor activities, and physiological effects. CBD is a nonpsychoactive cannabinoid with some analgesic, antiinflammatory, antineoplastic, and chemopreventive activities. THC is the primary psychoactive component with effects on euphoria, mood, and cognition.
THC was initially identified in the 1960s and has since been more thoroughly described, with the discovery of the primary molecules anandamide (AEA), 2-arachidonoylglycerol (2-AG), and fatty acid amide hydrolase. Subsequently, mechanisms on how those molecules work have been identified, particularly as it related to its interaction with pain modulation pathways. THC exerts its physiologic effects in the endocannabinoid (endogenous cannabinoid) system, interacting primarily with receptors CB 1 and to lesser degree CB 2 . CB 1 receptors are primarily localized in the central nervous system, but may also be found in the periphery, while CB 2 receptors are found in tissues of the immune system but may also be found in the brain ( Fig. 11.2 ). Cannabinoid and opioid receptors belong to the same rhodopsin subfamily of G protein-coupled receptors, which when activated inhibit adenylyl cyclase, leading to decreases in cellular levels of cyclic adenosine monophosphate.
Opioid and cannabinoid receptors are also localized primarily at the presynaptic nerve terminals, and when activated via cellular mechanisms, inhibit release of multiple neurotransmitters which may modulate pain pathways. They also colocalize in GABA-ergic neurons, the primary inhibitory neurons in the central nervous system. Activation of both opioid and cannabinoid receptors effects the permeability of calcium, potassium, and sodium channels, which may also explain how they may modulate pain pathways. , , Inhibition of glutamate release from nociceptive neurons and pain-associated regions is felt to be one of the primary antinociceptive mechanisms. Norepinephrine, 5-hydrotryptamine, glycine, and dopamine are other neurotransmitters, both opioids and cannabinoids may modulate and may have an impact on pain modulation. Opioids and cannabinoids have similar pharmacologic profiles which may cause hypothermia, hypotension, hypoventilation, sedation, and antinociception. , Naloxone is a mu-opioid inverse agonist as well as kappa- and gamma-receptor antagonist which has been shown to have effects on the cannabinoid system in multiple animal model studies. There have been case reports of treating cannabinoid overdose with naloxone infusion.
CBD has been receiving more attention recently due to its nonpsychoactive properties and its potential benefit for a narrow spectrum of pediatric seizures. Its benefits in pain have also been touted due to its possible impacts in inflammatory processes. Due to its molecular makeup, it does not bind well to the CB 1 or CB 2 receptors, although some of its analogs may have low binding affinity for that receptor. Some of the evidence supporting its antiinflammatory properties are its affinity to adenosine A2A, and GPR55 (G protein receptor 55) receptors which may modulate cellular calcium (Ca ++ ) and potassium (K + ) channels. Other signaling events in inflammatory processes identified in animal models include stimulating arachidonic acid release and phospholipid hydrolysis, stimulation of cyclo-oxygenase-2 (COX-2), reduction of prostaglandin E 2 (PGE 2 ), reduction of nitrous oxide (NO), and other oxygen-derived free radicals. In addition, signaling events may be related to CBD’s effect on cytokine production. The effects or benefit of purified CBD use in human inflammatory processes have not been rigorously evaluated.
A serious concern regarding the use of artisanal CBD products for medicinal purposes has much to do with “product integrity.” Currently, there is only one FDA-approved and purified CBD: Epidiolex. It is approved for Dravet and Lennox-Gastaut syndromes, effecting a very small percent of the pediatric population. It has been claimed that CBD is federally legal in all 50 states and can be purchased CBD online. It has been reported that medical CBD products purchased in regulated markets failed to meet basic label accuracy standards for pharmaceuticals. In those products, only 59% had detectable levels of CBD, only 17% were accurately labeled with respect to THC content, and only 17% had CBD content labeled. It has been further reported that CBD products purchased online, only 31% were accurately labeled and THC was detected in 21% of the samples, which is federally illegal to be mailed through the postal service.
With the expansion of multiple marijuana markets over the past several years, there appears to be an increasing inability to test and regulate marijuana products which are used for both medical and recreational purposes. In January 2019, the Oregon Secretary of State published an audit of their marijuana programs. They reported that the state was only able to inspect 3% of retailers and 32% of growers due to a variety of issues. There was a significant lack of testing for pesticides and solvents, as well as heavy metals and microbiological contaminants which could pose a consumer risk. They concluded that Oregon’s marijuana testing program could not ensure that test results were reliable or that products were safe.
Cannabinoids And Pain: Literature Review
Despite general restrictions on the study of cannabis from federal levels, there has been ongoing research on cannabis for decades since the discovery of its primary psychoactive component, THC, and subsequently identification of the many other components of the plant which may have potential physiologic activity. Reviews of the medical use of cannabinoids in several conditions have evaluated the evidence at the time. , , Currently, many countries are in the midst of an opioid epidemic and there are thoughts that cannabis may be a good opioid substitute and could potentially impact such epidemic.
In 2014, Bachhuber reviewed opioid overdose deaths in medical marijuana states and concluded that medical cannabis laws are associated with a significantly lower state-level opioid overdose mortality rates, however also felt more research is needed to evaluate the interaction between medical cannabis laws and opioid analgesic overdose deaths. In 2016, this was followed by Bradford’s research which suggested that medical marijuana laws are associated with lower Medicare D prescriptions and may have influenced opioid prescribing patterns and spending in Medicare Part D. In this day and age of health insurance, cost savings are important to take into consideration. They noted limitations of their study, which included the fact that Medicare D population comprised a very small percentage (13%–27%) of people who use medical marijuana, and physician prescribing behavior is difficult to quantify.
In 2017, Livingston looked at opioid-related deaths in Colorado between 2000 and 2015, utilizing the Centers for Disease Control and Prevention WONDER (Wide-Ranging Online Data for Epidemiologic Research) system. They found a statistically significant reduction of 6% in opioid-related deaths following recreational cannabis legalization in Colorado. A potential confounder they noted was Colorado’s prescription drug monitoring program registration mandate in 2014. In 2019, the Colorado Medical Society issued a report showing that PDMP utilization increased by 650% since marijuana legalization in 2014 and the rate of retail-filled opioid prescriptions had decreased to the lowest in 5 years, dropping almost 30% from 2013 to 2018. In that period of time, there has also been an increased physician and public awareness of the opioid epidemic, a significant increase in utilization of naloxone, the reversal agent for opioid overdose, development of atypical opioids, and abuse-deterrent formulations which have less abuse potential, and there may be an increase reluctance for physicians to prescribe, or patients to receive, an opioid prescription.
Despite those efforts and available data, Colorado had a record number of prescription opioid overdose deaths in 2017, with 2018 having the second highest number of deaths ( Fig. 11.3 ). It is important to understand that Colorado has had a medical marijuana program since 2001, and consistently over time, more than 90% of the marijuana recommendations were for a pain condition. Similar data have occurred in other marijuana states, such as Illinois, where their Department of Public Health has been tracking such data. Despite a steady decline in the number of opioid prescriptions, the number of opioid overdose deaths has continued to climb ( Fig. 11.4 and 11.5 ). Interestingly, in Colorado, since legalization for medical and subsequently for recreational use, the number of overdose deaths related to other drugs also increased, including cocaine, methamphetamine, heroin, and fentanyl. In 2018, they noted 16 overdose deaths mentioning marijuana, the highest ever. It is unclear as to the nature or circumstances of those deaths, including an incidental finding or possibly synthetic cannabinoid present.