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An August 2022 research study entitled "Practical Considerations for the Use of Cannabis in Cancer Pain Management—What a Medical Oncologist Should Know" that was published in the Journal of Clinical Medicine explored "the use of cannabis-based medicines for cancer pain management" with the goal of informing "the medical oncology community about the use of cannabis as a possible therapeutic option for pain relief."
The study noted that pain is an "unpleasant emotional and sensory experience that is associated with potential or actual tissue damage" and that about "70 percent of cancer patients experience pain, which impacts their emotional and physical dimensions." It added that the effective treatment of chronic cancer pain "requires a comprehensive approach that includes both non-pharmacological and pharmacological modalities."
The researchers explained that opioids "are the foundation for managing moderate and severe cancer pain," but that they unfortunately also convey "many side effects" and a risk of addiction. Therefore, "opioid-based pain management requires close monitoring."
Cannabis-based Medicines Explored
The researchers explained that "alternative pharmacological interventions" exist for the treatment of cancer pain, including "cannabis-based medicines." They noted that these include "plant-derived cannabinoids, synthetic cannabinoids, magistral preparations of cannabis plant derivatives, nutritional supplements, and experimental medications."
CBD and THC "are the most studied compounds in the cannabis family" and can be administered "orally as capsules or oils, via inhalation, or as a spray under the tongue."
The study noted that cannabidiol (CBD) and delta-9 tetrahydrocannabinol (THC) "are the most studied compounds in the cannabis family" and that they can be administered "orally as capsules or oils, via inhalation, or as a spray [or liquid tincture] under the tongue."
However, the pharmacology of cannabinoids remains limited. The various delivery systems and routes, along with the different concentrations of cannabinoids, make prediction of efficacy challenging for medical professionals.
Cancer Pain Types
"Pain affects 50–90 percent of cancer patients and is one of the most disabling symptoms," noted the study's authors. Cancer pain is categorized as either neuropathic or nociceptive and features "a complex pathophysiology."
The neuropathic variety of pain "can result from direct tumor invasion of nervous tissues, post-irradiation plexopathies, or chemotherapy-induced peripheral neuropathy." The study reported that patients describe neuropathic pain as an "electric or burning sensation, and sometimes as muscle weakness. It often manifests as persistent background pain" and has been found to often be "unresponsive to opioids."
Pain Assessment & Opioids
The assessment of pain in cancer (and all types of) patients "usually requires the use of a visual analog scale (VAS) from 0 to 100 mm or a numerical rating scale (NRS) from 0 to 10. Scientists consider a reduction in pain intensity that exceeds 30 percent (20 mm on the VAS or 2 points on the NRS) to be considered "a clinically significant improvement."
The study reported that cannabis "has a long history of medicinal use" and that CBD and THC "are the two components with the highest concentrations in cannabis."
The most common treatment for cancer pain is "strong opioids, including morphine." The researchers explained that opioids "are the mainstay of moderate-to-severe cancer pain management."
Cannabis for Pain
The study reported that cannabis "has a long history of medicinal use" and that CBD and THC "are the two components with the highest concentrations in cannabis." It noted that these phytomolecules bind with specialized microscopic cellular receptors (G protein coupled receptors) in the human endocannabinoid system (ECS) called CB1 and CB2.
The research noted that these ECS receptors are designed to bind with cannabinoids manufactured by the human body called endocannabinoids (or endogenous ligands) that includes 2-arachidonoylglycerol (2-AG) and anandamide (AEA). Phytocannabinoids produced by hemp and cannabis mimic these endocannabinoids. More specifically, delta-9 THC mimics anandamide and CBD acts like 2-AG.
The study reported that cannabinoids (the endo or phyto variety) and the ECS overall are intimately involved in "several physiological and pathological conditions" that include appetite, fertility, memory, immune system, cancer, and pain management.
CB1 and CB2 receptors are found in nearly all areas of the body, but CB1 are most dense in the brain and central nervous system, particularly the amygdala, basal ganglia, cerebellum, and hippocampus.
Both CB1 and CB2 receptors are found in nearly all areas of the body, but CB1 are most dense in the brain and central nervous system (CNS), particularly the amygdala, basal ganglia, cerebellum, and hippocampus. "CB1 receptors are located predominantly in the presynaptic membrane and are, therefore, modulators of synaptic release," reported the study.
CB2 receptors are found in the largest numbers in what scientists call the periphery, or the area outside of the brain and CNS. CB2 receptors are most dense in the organs, tissues, and glands related to the immune system (the majority of the body).
ECS Receptors, CBD, & THC
The scientists explained that both endocannabinoids such as 2-AG and anandamide and phytocannabinoids like CBD and THC target multiple receptor types within the human body, well beyond CB1 and CB2. These types of receptors include GPR18, GPR55, TRPV receptors (transient receptor potential vanilloid; TRPV1 through TRPV4), and even serotonin and opioid receptors.
"THC has an affinity for the CB1 and CB2 receptors similar to that of AEA," noted the researchers. "In addition to its psychoactive effect, THC is responsible for most of the pharmacological outcomes of cannabis, including analgesic, antioxidant, anti-inflammatory, bronchodilator, antipruritic, and anti-spastic activities," reported the scientists.
The study classified CBD as "the second most abundant component of cannabis" and claimed that it "has broader medical applications than THC." One of the most obvious differences in the efficacy of CBD and THC is psychoactivity, which the former molecule lacks and the latter provides abundantly (especially in potent doses and for novice users who have not built a tolerance). Despite its lack of psychoactivity, the study noted that CBD "has been reported to reduce inflammation, muscle spasms, seizures, and anxiety."
Despite its lack of psychoactivity, the study noted that CBD "has been reported to reduce inflammation, muscle spasms, seizures, and anxiety."
The study reported that CBD "has a poor affinity for cannabinoid receptors and its mechanism of action is different from that of the endocannabinoid system." In terms of pain management, however, "studies have indicated that CBD can regulate pain perception by interacting with other G-coupled receptors, including δ-opioid, μ-opioid, and dopamine receptor D2."
Cannabinoid Onset & Bioavailability
The research investigation further described cannabinoids as "highly lipophilic [fat loving] substances that are stored in spleen and adipose [fat] tissues." When consumed via inhalation (smoking or vaporization), "peak plasma levels of CBD and THC are rapidly achieved within 3-10 minutes." The study reported that bioavailability of THC (how much reaches the bloodstream to become active and produce real effects "varies considerably due to the differences between cannabis products and inhalation techniques, ranging between 10 and 35 percent."
Inhaled CBD, on the contrary, featured an average bioavailability of 31 percent. When ingested (eaten), the study reported that both CBD and THC achieve peak plasma levels in approximately one to two hours and the bioavailability is "considerably lower than that obtained by smoking due to hepatic first-passage metabolism" that occurs in the stomach and liver.
"When inhaled by smoking, the analgesic [pain reducing] effect of cannabinoids is experienced shortly after the first breath," reported the scientists, who also noted that smoking (combustion) constitutes "a significant disadvantage and may negatively affect the respiratory tract." Other studies have cited a two to 2.5-minute onset period for inhalation of cannabinoids.
In spite of the health risk of smoking, "the major limitation of oral [ingested] cannabinoids is their...highly variable absorption, slow onset of clinical effects, and unpredictable psychoactive effects."
Although federal-level prohibition of cannabis has existed in the United States in some form since 1937, the study's authors explained that "several cannabinoid drugs have been developed to date" that include Nabiximols (Sativex®), "an almost 1:1 ratio of plant-based THC and CBD" that is prescribed for the treatment of spasticity in multiple sclerosis. Epidiolex is an oral CBD product used in the treatment of severe pediatric epilepsy, including Dravet syndrome and Lennox-Gastauld syndrome.
"The major limitation of oral [ingested] cannabinoids is their...highly variable absorption, slow onset of clinical effects, and unpredictable psychoactive effects."
In addition to Sativex and Epidiolex, dronabinol and nabilone are synthetic forms of THC that have been approved for the treatment of "chemotherapy-related nausea and vomiting" and to combat excessive weight loss in patients with AIDS.
Pain #1 Reason for Cannabinoid Use
According to the study, the "most documented reason for cannabinoid use" is relief from pain. It explained that the pain from cancer "is often chronic, with inflammatory, nociceptive, and neuropathic components." It explained that interest in cannabinoids for pain has increased within the scientific community due to the need for "safer therapeutic options" and "novel non-opioid" solutions.
The study reported that cannabinoids "demonstrate greater potency" for neuropathic pain and pain resulting from inflammation than for acute or physiological pain. Roughly 40 percent of patients who suffer cancer-related pain experience the neuropathic variety. It explained that those who suffer peripheral nerve damage feature more—and more active—CB1 and CB2 receptors in their ECS and that such patients experience "positive effects of cannabinoids...on neuropathic pain."
Cannabis for Cancer Pain Studies
"The first placebo-controlled [study] trial published in 1975 reported that 15 and 20 mg THC oil provided more pain relief than placebo in a group of 10 patients with cancer treated with opioids (mainly methadone)."
Another previous pain study reviewed by the current investigation included 36 human subjects and concluded that "the amount of pain relief produced by 10 mg of THC oil was comparable to that resulting from 60 mg of codeine." Despite this benefit, THC is sometimes viewed as a double-edged sword due to its potential negative side effects, which have been found to include "dizziness, ataxia [poor muscle control that causes clumsy voluntary movements"], somnolence [a state of drowsiness and sleepiness], and blurred vision."
"The amount of pain relief produced by 10 mg of THC oil was comparable to that produced by 60 mg of codeine."
The study explained how, in addition to inhalation and ingestion, "oromucosal sprays have been widely used in clinical trials to administer cannabis-based medicines." One prior study involved oral administration of nabiximols (Sativex®) to 177 "advanced cancer patients" who demonstrated a "statistically significant improvement in the mean pain score." The research also revealed that patients treated with nabiximols "required fewer doses of breakthrough pain medication."
Another study investigated the analgesic efficacy of nabiximols via a "double-blind, randomized, placebo-controlled trial on cancer patients suffering from severe pain" that was "poorly controlled by opioids." The study revealed "enhanced synergy between cannabinoids and opioid receptors" that resulted in improved pain management.
A comprehensive study conducted in Israel "evaluated the safety and efficacy of medical cannabis in 3,619 cancer patients" who received a unique mixture of "16 THC and CBD strains administered with various concentrations of oils and/or inflorescences [a group or cluster of flowers] (including capsules, loose-leaf flowers, and cigarettes)."
After one month of treatment, about 20 percent of the study participants "reported a moderate improvement" and 66 percent reported a "significant improvement in their general condition." About eight percent of study subjects experienced side effects, including confusion, cough, disorientation, dizziness, nausea, and tiredness.
"After six months of treatment, 45 percent of study participants reported moderate improvement in pain and 51 percent reported significant improvements."
After six months of treatment, 45 percent of study participants reported moderate improvement in pain and 51 percent reported significant improvements. In addition, 69 percent of study participants reported "good quality of life" compared to the study's baseline, which was only 19 percent.
Cannabinoids Decrease Opioid Use
"More importantly, 10 percent of the patients reported a decrease in opioid dose and 36 percent discontinued opioid use." Over the course of the entire study, about 30 percent of patients "reported at least one side effect" and that these included "dry mouth, dizziness, sleepiness, increased appetite, and psychoactive effects."
"10 percent of cancer patients reported a decrease in opioid dose and 36 percent discontinued opioid use altogether."
The study also reported that research indicates that U.S. states with medical cannabis regulations "witnessed a slower increase in opioid analgesic overdose-related mortality."
The Reality of Cannabis Addiction
The study reported that cannabis use by patients "has been extensively debated based on the presumption that it can lead to dependence and addiction." Both apologists who claim that cannabis never results in addiction and critics who claim that addiction rates are extremely high ("epidemic levels") are wrong.
Multiple research studies reveal that roughly nine percent of "all people who have ever used cannabis will experience dependency at some point in their lives."
The study's authors observed that, globally, "the legal context of the use [of cannabis] is becoming more permissive." They noted that the World Health Organization has proposed the rescheduling of the controversial herb within international laws. Individual nations are migrating their oversight in this direction, with "many European countries, Thailand, Canada, and almost three-quarters of the U.S." making medical cannabis legal.
Multiple research studies reveal that roughly nine percent of "all people who have ever used cannabis will experience dependency at some point in their lives."
"Cancer pain is a highly debilitating syndrome that has a significant impact on quality of life and is sometimes challenging to treat using available therapeutic options," concluded the study. It explained that cancer pain is becoming more common due to "remarkable improvements in therapies" and "life-saving interventions (surgery, chemotherapy, and radiotherapy)." Because survival rates and life expectancies for cancer patients are increasing, management of their pain is becoming a more important issue.
The researchers recommended additional clinical studies regarding the treatment of pain from cancer with cannabinoids and other chemical components of the cannabis and hemp plants. "Further clinical trials, more extensive and more rigorous, are needed to establish their clinical efficacy, dosing, and, not least, their potential interactions with other drugs," stressed the study's authors.
View the original study.