The Use of Medical Marijuana for Pain in Canada
Cannabis sativa (cannabis) has been used as a medicinal agent for almost 5,000 years in traditional Eastern medicine. Its introduction into Western medicine took place in 1841 as a result of the work of William O’Shaughnessy, an Irish physician who encountered “Indian hemp” in Calcutta. By the late 19th century, pharmaceutical companies in the Americas were producing medical cannabis in the form of cannabis-based extracts, tinctures, cigarettes, and plasters.1,2 These agents were mainly indicated for a wide range of conditions, many related to pain.3,4
In 1892, a leading Canadian internist, Sir William Osler, wrote in The Principles and Practice of Medicine that “Cannabis Indica is probably the most satisfactory remedy for migraines.”5 Despite these benefits, the medical use of cannabis fell from favor, and in the 1930s and 1940s was widely banned around the world.1 More recently, the medical use of cannabis has re-entered the market in several countries for the treatment of a variety of conditions, including pain.6,7
Support for Medical Cannabis
There appears to be a surge in evidence supporting the medicinal use of cannabis, in part due to patients reporting significant pain relief and reduction in the use of other medications, including opioids. In a large survey of medical cannabis users in Arizona with chronic pain, 77% of fibromyalgia patients, 63% of patients with arthritis, and 51% of patients suffering from neuropathic pain reported experiencing “a lot” or “almost complete overall relief” of their painful condition.8 These were subjective measures (no numeric or visual-analogue rating scales were applied before or after used).
Reduced usage of other medications, as described as “a little or much less frequency,” was found in 94% of patients with fibromyalgia, 81% of arthritic patients, and 61% of patients with neuropathy who used medical cannabis. Moreover, 75% of medical cannabis users who experienced opioid dependency reported a lot or almost complete overall relief.8 These findings highlight the wide range of clinical uses for medical cannabis, as well as the value of such studies at a time where evidence from controlled clinical trials is still emerging.
In the United States, the federal government still classifies cannabis, along with heroin, as a Schedule I drug; that is, as having a high potential for abuse and no recognized medical use. At the same time, 25 states and the District of Columbia have legalized marijuana for medical or recreational use.9 Each state has its own laws for recommending, dispensing, and possessing medical marijuana. [Editor’s Note: The Drug Enforcement Agency is weighing whether to downgrade its classification of medical marijuana from Schedule I to Schedule II.]
Cannabis and Pain: Mechanistic Considerations
The cannabis plant contains many biologically active components, including over 60 cannabinoids.10 There are 3 types of cannabinoid molecules that bind to cannabinoid receptors. These include: phytocannabinoids, which are obtained from the cannabis plant; synthetic cannabinoids (such as nabilone [Cesamet], a synthetic nitrogen analogue of delta-9-tetrahydrocannabinol [THC]); and endogenous cannabinoid receptor ligands, also known as endocannabinoids. THC, a phytocannabinoid, is the primary psychoactive
component found within cannabis that has been shown to have analgesic effects (Figure 1).11
Further, there is increasing evidence highlighting other medicinal properties for other phytocannabinoids. In particular, cannabidiol (CBD), a nonpsychoactive molecule, has been shown to have anti-inflammatory12 and analgesic13,14 properties. THC and CBD are biosynthesised from a common precursor as delta-9-tetrahydrocannabinoilic acid (THCA) and cannabidiolic acid (CBDA), respectively,15 and require heat or extraction to undergo decarboxylation to produce THC and CBD properties.16 Other phytocannabinoids with potential therapeutic effectss include cannabigerol, cannabichromene, cannabinol, cannabidivarin, and tetrahydrocannabivarin (Figure 2, above).17
THC mimics the action of the endogenous cannabinoids anandamide and 2-arachidonylglycerol (2-AG).18 Both THC and anandamide are partial agonists of cannabinoid type 1 (CB1) receptors,16,18 which are primarily expressed in the central nervous system, particularly in areas related to pain, such as the spinal trigeminal nucleus, amygdala, basal ganglia,19 and the peri-aqueductal gray.20,21
At the cellular level, the central nervous system’s expression of CB1 receptors are localized on the terminals of presynaptic neurons.22 The endocannabinoids that bind to them act as retrograde signaling agents; that is, they are synthesized postsynaptically and move backward across the synapse to inhibit presynaptic neurotransmission.23 It is believed that THC induces analgesia by inhibiting neurons activated by pain in regions associated with nociception by binding presynaptic CB1 receptors (Figure 3).
As mentioned previously, CBD has intrinsic analgesic and anti-inflammatory properties13,14,24 and antagonizes several adverse effects of THC, including sedation,16,25 tachycardia,16,26 and anxiety.27 CBD also ameliorates the psychoactive effects of THC,27 an issue for many medical cannabis patients. It achieves this by slowing the conversion of delta-9-THC to the more psychoactive
delta-11THC. Unlike THC, CBD has low affinity for CB1 receptors28 and exerts analgesic actions by binding multiple proteins related to pain. For example, CBD has been shown to bind TRPV1 (Transient Receptor Potential Cation Channel, Subfamily V, Member 1), to mediate its desensitization, and to inhibit inactivation of anandamide,28 both of which contribute to analgesia. CBD is a potent anti-inflamatory agent and may indirectly induce analgesia by limiting inflammation at the site of injury.12
While there is substantial preclinical evidence showing that smoking cannabis is beneficial in treating chronic pain conditions, including osteoarthritis, rheumatoid arthritis, fibromyalgia, and cancer, no randomized controlled trials (RCTs) have been carried out for these conditions.29 However, to date, there have been 5 RCTs that have evaluated the analgesic efficacy of cannabis for patients with neuropathic pain.30-35