Cannabis has been used for medicinal purposes for thousands of years. However, the prohibition of cannabis in the mid-20th century interrupted the flow of research in the field. Fortunately, in recent years, the debate about the use of cannabis for medicinal purposes has gained traction, and legalization in various countries has propelled research. The term “medical cannabis” refers to the use of the Cannabis sativa plant and its components, called cannabinoids, recommended by a physician to treat diseases or improve symptoms. Chronic pain is the most commonly cited reason for cannabis use.

Phytocannabinoids, derived from the plant, can mitigate various types of pain in all their complexities in unique ways, as cannabinoid receptors are widely distributed throughout the different pain-modulating pathways in the human body. These include central and peripheral sensory neurons, brain regions that modulate sensory discrimination, pain-regulating circuits in the brainstem, and affective states that regulate emotional responses to harmful stimuli. Due to its broad and complex actions, cannabis in its complete form (full spectrum extracts and natural products) can be considered a polypharmacy on its own, kindly provided to us by nature through thousands of years of evolution.

Additionally, endocannabinoids (produced by our own body) can respond to pain by unlocking one or more of the first therapeutically available pathways to achieve analgesic effects, with clinical data indicating analgesic efficacy in chronic pain of various etiologies.

Understanding the Endocannabinoid System (ECS)

The endocannabinoid system (ECS), first described in the early 1990s, is a cell signaling system composed of endocannabinoids, cannabinoid receptors, and enzymes responsible for the synthesis and degradation of endocannabinoids. It is present throughout the central nervous system of vertebrates, including the brain, and in the peripheral nervous system, including organs, tissues, and immune cells.

Endocannabinoids are lipidic compounds produced by the body that bind to cannabinoid receptors present in cells. The main endocannabinoids are N-arachidonoylethanolamine (AEA or anandamide) and 2-arachidonoylglycerol (2-AG). The two main cannabinoid receptors, which are G protein-coupled receptors, are CB1, found mainly in the brain and central nervous system, and CB2, found primarily in immune system cells and peripheral tissues. In addition to these, other receptors that have been described are GPR55, GPR18, GPR119, TRPV1, TRPV2, and FAAH.

Endocannabinoids are produced on demand and can be immediately released from cells, regulating excitatory and inhibitory synaptic transmission. In the central nervous system, endocannabinoids act as neurotransmitters, released from depolarized postsynaptic neurons and traveling to presynaptic terminals, where they activate CB1 receptors through a retrograde signaling mechanism. The overall effect is a decrease in neurotransmitters such as GABA and glutamate. This mechanism indicates the endocannabinoids’ crucial modulatory role in maintaining body homeostasis.

Therefore, the ECS is crucial in regulating many physiological functions. Through genetic and pharmacological studies, endocannabinoids were discovered to act as neuromodulators for various processes, including pain sensation, mood, appetite, sleep, memory, motor control, reproduction, the immune system, and inflammation. In other words, endocannabinoids and cannabinoid receptors interact with cellular signaling systems, such as the nervous, immune, and endocrine systems, modulating their functions. For this reason, the ECS is involved in

.

Genetic and pharmacological studies discovered that endocannabinoids act as neuromodulators for several processes, including pain sensation, mood, appetite, sleep, memory, motor control, reproduction, the immune system, and inflammation. In other words, endocannabinoids and cannabinoid receptors interact with cellular signaling systems, such as the nervous, immune, and endocrine systems, modulating their functions. For this reason, the ECS is involved in various pathologies, including neurodegenerative diseases, anxiety and depression disorders, eating disorders, inflammatory diseases, and chronic pain.

Applications in Pain – What Research Says

Currently, 227 primary studies directly examine components of the endocannabinoid system concerning chronic pain, with 44 being clinical studies and 139 preclinical studies, with 87% reporting overall positive results (source: Cannakeys Platform). The European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) already identifies cannabinoid therapy as a treatment for chronic pain. The UpToDate platform also includes phytocannabinoids as a therapeutic option for chronic pain.

A systematic review and meta-analysis published in JAMA in 2015 revealed that cannabis significantly reduced chronic pain. This comprehensive study analyzed 28 randomized clinical trials involving over 2,000 participants, where cannabis was used in different formulations, including products with CBD, THC, and both. Some conditions evaluated within chronic pain were neuropathic pain, fibromyalgia, rheumatoid arthritis, musculoskeletal pain, cancer-related pain, and multiple sclerosis-associated pain. The study concluded that there is moderate-quality evidence for the indication of cannabis for chronic pain and spasticity, with an average pain reduction of 30% compared to a placebo. An important point to highlight is that the adverse effects observed in the study are commonly associated with high doses of THC and uncommon in the use of CBD.

Chronic pain is a challenging condition to manage, often leading to the development of other pathologies such as anxiety, depression, and insomnia. A 2023 cohort study evaluated the efficacy of cannabis in 1254 patients with chronic pain, with and without comorbid anxiety, finding improvement in all patients, but with a more pronounced perception of improved quality of life in the group with anxiety. Other interesting findings in this study were the reduction, in all groups, of opioid medication consumption and an acceptable level of adverse effects. Despite the inherent limitations of any observational study, these results add to several others, indicating significant potential for the use of cannabis in treating chronic pain of various origins and associated conditions.

Another rigorous systematic review published in the Global Spine Journal in 2022 also found positive results when evaluating the evidence and effectiveness of cannabis use in the management of both surgical and non-surgical spinal pain. Another study also observed improvement in patients suffering from low back pain associated with disc herniation and spinal stenosis. To conclude, a phase II study reported improvement in patients with basal joint arthritis of the thumb after using topical CBD.

The list of positive evidence for using different cannabis products for various types of pain is extensive. And while we still need more rigorous and long-term studies, the potential of this therapy, either as an adjuvant or primary treatment, is evident, especially in refractory cases.

Mechanism of Action

The distribution of cannabinoid receptors in the human body provides the anatomical basis for understanding the analgesic effects of endogenous and exogenous cannabinoids. The presynaptic activation of CB1 receptors in different brain regions or primary afferents inhibits the release of neurotransmitters by decreasing calcium conductivity and increasing potassium conductance.

Endocannabinoids, in turn, modulate pain under physiological conditions. Therefore, pharmacological approaches that increase endocannabinoid levels by inhibiting the enzymes that control endocannabinoid deactivation or blocking their reuptake exhibit great therapeutic potential.

THC is undoubtedly the most studied cannabinoid for pain, acting more directly on metabolic pathways and having its action tested and proven. THC is also responsible for most undesirable adverse effects, although not in all cases, and for the psychoactive effects commonly associated with recreational cannabis use. On the other hand, CBD has various mechanisms of action in the human body that extend beyond the limits of the endocannabinoid system. Its anti-inflammatory, analgesic, and anxiolytic actions are widely reported in the literature. Additionally, CBD has a very safe profile, with rare, mild, and mostly transient adverse effects, even at higher doses. In addition to these two main compounds, other natural cannabinoids, such as CBG and CBN, also have promising effects on pain and are receiving growing attention from researchers.

Cannabinoids and Opioids

In 2019 alone, 70,000 people died from overdose in the United States, with the majority of deaths attributed to opioids. A study published in JAMA in 2014 indicates that 60% of opioid-related deaths occur in individuals without a history of abuse, meaning they are accidental deaths of people seeking pain relief. The opioid crisis is a serious and urgent issue. Preliminary research results suggest a possible synergy between CBD, THC, and opioids, potentially allowing for combined analgesic effects, reducing opioid dosages, and the risks of adverse effects. A prospective US study from 2022 followed 115 patients for six months in concurrent therapy and showed an average reduction of about 70% in daily morphine consumption. Another 2022 study, a meta-analysis involving patients with chronic low back pain, indicated a decrease in opioid use and an improvement in pain scores and disability with cannabinoid therapy. Furthermore, a German study followed elderly patients in a pain clinic for three years, also finding a reduction in opioid use and good tolerance of cannabis products by the patients.

In US states where cannabis use is regulated, a 25% decrease in opioid overdose deaths has been observed. Motivated by this and other statistics, a multidisciplinary team from the US and Canada developed the first clinical guidance with practical steps to introduce cannabinoid-based therapy during opioid management in chronic pain.

Adjuvant approaches using phytocannabinoids show strong promise in improving the effectiveness of existing pharmacotherapies for pain and limiting undesirable side effect profiles. Understanding our endocannabinoid system opens up many new therapeutic possibilities, and cannabis is increasingly proving an effective and safe alternative for managing chronic pain.

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