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15 Articles in Volume 19, Issue #3
Analgesics of the Future: The Potential of the Endocannabinoid System
Buprenorphine: A Promising Yet Overlooked Tool
Chronic Pain and the Psychological Stages of Grief
Could a Personalized Approach to Therapy End the War on Pain?
Finally, A Systematic Classification of Pain
Hormone Therapy for Chronic Pain
How to Communicate with a Medical Marijuana Dispensary
Letters: Opioid Conversions; Scrambler Therapy for CRPS
MSK Pain: Time for an Enhanced Assessment Model
National Drug Use & Abuse Trends: Prescribed and Illicit
Neuroplasticity and the Potential to Change Pain Response
Should Emergency Naloxone Be in Schools?
Talking to Patients about Medical Cannabis
Utility of Pulsed Radiofrequency Ablation in Xiphodynia
When Opioid Prescriptions Are Denied

Analgesics of the Future: The Potential of the Endocannabinoid System

A look at the endo-, phyto-, and synthetic cannabinoids currently available, including CB1 and CB2 receptor agonists
Pages 56-62

Cannabis has been used throughout history for an array of reasons, including analgesia, psychiatric conditions, and seizures. Some patients may also use cannabis recreationally, more commonly known as marijuana. The US government has traditionally regulated cannabis use closely, perhaps more so than any other plant with medicinal utility. However, over the early part of this century, there has been a push for increased research as the number of cannabis users continues to rise. This growth has resulted in seemingly annual changes in regulation revolving around the use of cannabis in the majority of states.

It is important to consider that marijuana is still classified as a Schedule I controlled substance under federal law. Despite the implications this has on the research of the cannabis plant, great efforts have been made to explore ways that cannabis-based chemicals may be used to treat a variety of diseases, as well as their interactions with the human body. This review aims to share how cannabinoids interact with the human body and to differentiate potential therapeutic targets (both FDA approved and pipeline candidates), with a focus on ongoing drug development in the realm of pain management.

The Endocannabinoid System

Traditionally, the term cannabinoid was used to define a group of compounds derived from specific cannabis plant strains. Today, it is used more wholly to categorize all types of molecules with effects on human cannabinoid receptors, including phytocannabinoids (plant-based), endocannabinoids (produced endogenously in humans), and synthetic analogs of both groups.1-3 To fully appreciate the effects that different cannabinoids may have, an understanding of the human endocannabinoid system is essential.

It was not until the 1990s that research led to the discovery of the endocannabinoid system within the human body. It was revealed that different cannabinoids have an ability to bind and activate specific G protein-coupled, membrane-bound receptors; mainly cannabinoid type 1 (CB1) and cannabinoid type 2 (CB2).1,4,5 CB1 receptors are primarily found throughout the central nervous system (CNS) including within the cerebral cortex, amygdala, hippocampus, basal ganglia, substantia nigra, and cerebellum, as well as along nerve terminals and in peripheral cells including the uterus, prostate, testis, stomach, endothelium, and skeletal system.1,6,8 Alternatively, CB2 receptors are less ubiquitous and tend to be primarily expressed by various immune cells (eg, B cells, natural killer cells, neutrophils) where their level of expression is dependent upon stimulation of the immune system.6,9 Recent research has shown that CB2 receptors also exist within certain areas of the peripheral and central nervous system, including the dorsal root ganglia, lumbar spinal cord, and microglia.10

The CB1 and CB2 Receptors

Activation of CB1 receptors is postulated to affect analgesia by diminishing excitatory postsynaptic neuronal transmission, increasing vascular smooth muscle vasodilation, and decreasing release of a multitude of pro-inflammatory mediators.9,11,12 CB1 is also the receptor associated with the psychotropic effects of cannabinoid products. Activation of CB2 receptors has been shown to modulate the immune system by inducing cellular apoptosis, suppressing cellular proliferation, inhibiting pro-inflammatory mediator production, and inducing regulatory T-cells.9,13 These actions are primarily seen without the psychotropic effects associated with agonism of CB1 receptors.9 The lack of psychotropic-related effects from CB2 receptor activation, as well as the downstream neuro-inflammatory modulation, has resulted in an increased interest in developing products that target CB2 receptors.

Endocannabinoids: 2-AG and AEA

There are a multitude of endogenously produced cannabinoids that have effects on the CB1 and CB2 receptors, including the well-known 2-arachidonoylgylcerol (2-AG) and anandamide (AEA) (see Table I for further detail). 2-AG is primarily synthesized from diacylglycerol via the enzyme diacylglycerol lipase, whereas AEA is synthesized from N-arachidonoyl phosphatidylethanolamine via the enzyme phospholipase D.1,3 From a biological perspective, 2-AG is known to activate both CB1 and CB2 receptors, whereas AEA more preferentially activates CB1 receptors.1,14 Recent research has shown that AEA also has off-target activity on transient receptor potential vanilloid 1 (TRPV-1) channels, which co-localizes with CB1 and CB2 receptors in nervous tissues, including peripheral sensory afferents, the spinal cord, periaqueductal gray matter (PAG), and within the cingulate cortex.15-18 Although TRPV-1 co-localizes with both types of cannabinoid receptors, its sensitivity increases in the presence of tissue damage and inflammation, and is highly associated with pain nociception.18 The activation of TRPV-1 has been associated with decreasing the total antinociceptive effect that cannabinoids may elicit.18

The metabolism of both 2-AG and AEA is also important to consider within the context of potential drug development. Monoacylglycerol lipase (MAGL) is an enzyme found on presynaptic nerve terminals and fatty acid amide hydrolase (FAAH) is an enzyme found post-synaptically, and both are mainly responsible for degradation of 2-AG and AEA, respectively.1,3,19,20 Expression of both enzymes has been shown to be somewhat dependent on peripheral nerve or tissue injury.1,3,21-23 Furthermore, it has been identified that cyclooxygenase enzyme-2 (COX-2) is involved in the metabolism of AEA into pro-inflammatory prostaglandins, which adds another layer of complexity to this system.17

Certain transport proteins have also been found to play an important role in the endocannabinoid system. Fatty acid binding protein 5 (FABP5) appears to enhance cellular uptake of AEA, which promotes the hydrolysis of AEA into arachidonic acid. This not only reduces brain endocannabinoid levels, but also increases the pro-inflammatory effects of arachidonic acid. FABP5 has additionally shown an ability to bind to arachidonic acid and mobilize it to cellular nuclei and, in particular, PPAR-beta-delta, resulting in the production of pro-inflammatory gene expression.24

Phytocannabinoids: THC and CBD

A full review of phytocannabinoids is outside of the purview of this article, however, they do play an important role given the ever-changing political climate. Cannabis itself is made up of more than 500 different types of phytocannabinoid constituents, the two most studied being delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD).2,25 The primary difference between the two is that THC agonizes both CB1 and CB2 receptors, and CBD more preferentially agonizes CB2.2 The metabolism of both appears relatively complex, however, THC is metabolized via both phase I and phase II enzymes into more than 100 metabolites with 11-OH-THC (equipotent) and THC-COOH being the most prevalent.26 Similarly, metabolism of CBD also involves both phase I and phase II enzymes into over 30 different metabolites, with the primary metabolites being 7-OH-CBD (active) and 7-COOH-CBD (inactive).26 In general, cannabis plant species have varying concentrations of THC, CBD, and other constituents; thus different types of cannabis may exert different physiologic effects.

Although complex, the endocannabinoid system as a whole has sparked a growing interest in the emergence of pharmacologic targets involving the synthesis of, degradation of, or endocannabinoid ligands themselves and their viability in treating several disorders.

Currently Approved Cannabinoid Products for Medical Use

To date, the only FDA-approved products working on the endocannabinoid system are synthetic cannabinoid compounds. These include dronabinol (Marinol), nabilone (Cesamet), and the recently approved cannabidiol (Epidiolex), which is a purified derivative version of CBD. Dronabinol and nabilone are probably the most similar, as both are synthetic versions of the chemical THC.27 Both medications are FDA approved for nausea and vomiting associated with cancer chemotherapy in patients who have failed to respond to conventional antiemetic treatments.28,29 Dronabinol is additionally approved for anorexia associated with weight loss in patients with AIDs and comes in a liquid formulation (Syndros).29 Epidiolex, alternatively, is a purified derivative version of CBD (appropriately named, cannabidiol) and was FDA-approved for the treatment of two rare types of epilepsy, Lennox-Gastaut Syndrome and Dravet Syndrome.30

Although none of the above products carry indications for analgesia, there has been some research and review with dronabinol and nabilone of their potential antinociceptive effects. Unfortunately, much of this research, like many medications studied for the treatment of pain, has met conflicting results. See review articles for further assessment of clinical trial data (Fraguas-Sanchez AI, et al, Drugs, 2018; Aviram J, et al, Pain Physician, 2017; Hill KP, JAMA, 2015). Overall, the majority of these studies have been non-conclusive in nature due to limitations, flaws, and biases, and as a whole, have indicated that further research is warranted.

Sativex (nabiximols) is a synthetic, oromucosal spray that contains THC and CBD extracts from the plant Cannabis sativa at a 1:1 ratio currently seeking FDA approval.3 This medication offers a wealth of efficacy and safety data associated with its use in pain conditions, and is specifically approved for multiple sclerosis (MS) spasticity in more than 25 countries, including Canada, Mexico, and several European countries.3 Additionally, in Canada, it has indications for relief of neuropathic pain in MS and pain in patients with advanced cancer.3 Recently, the developers of Sativex, GW Pharmaceuticals, launched Phase III clinical trials in the US, as they are seeking FDA approved indication for the treatment of MS spasticity and neuropathic pain conditions.31

Medical Cannabinoids in Development CB1 and CB2 Receptor Agonists

As described above, the majority of botanical and pharmaceutical product candidates act by directly agonizing the endocannabinoid receptors themselves. Most phytocannabinoids and synthetic cannabinoids (dronabinol and nabilone) non-selectively activate both CB1 and CB2 receptors, thus have relatively narrow therapeutic windows, limiting overall potential for use.

One theory behind circumventing this issue was to develop products that preferentially activate CB2 receptors. Epidiolex (cannabidiol), for instance, has shown good efficacy and tolerability in studies for the treatment of Lennox-Gastaut syndrome and Dravet syndrome, as noted above, however, literature is not available regarding its potential impact for pain conditions.3,33 APD371 (Olorinab), however, is another highly-selective CB2 receptor agonist developed by Arena Pharmaceuticals, that is currently in Phase IIb clinical trials for the treatment of visceral gastrointestinal pain.34 Results to date have appeared positive overall, with statistically significant improvements in abdominal pain over 8 weeks of treatment while remaining generally well-tolerated.35 JBT-101 (Lenabasum) is an oral, small-molecule, CB2 receptor agonist developed by Corbus Pharmaceuticals in Phase III trials for the treatment of systemic sclerosis and dermatomyositis, and phase II trials for systemic lupus erythematosus and cystic fibrosis.36,37 Although the company of JBT-101 is not currently seeking specific indications to treat pain conditions, its basis for the above diseases is to resolve innate immune responses and decrease cytokine production, and Phase II trial data has shown favorable safety data thus far.38,39

Another approach among drug developers has been to avoid the central or psychotropic effects that occur with traditional CB1 agonisms by creating peripherally selective agents. One pipeline compound, co-developed by NeoMed Institute and Artelo Biosciences, NEO1940/ART27.13,10 is a potent agonist of CB1 and CB2 receptors with limited CNS penetration that is in Phase II trial planning for multimodal supportive care therapy for cancer patients and cancer-related anorexia.40,41 Importantly, five Phase I clinical studies demonstrated statistically significant and dose-proportional increases in body weight (efficacy outcome).40 Corbus Pharmaceuticals has another pipeline product, CRB-4001, which is a second generation, peripherally-restricted, CB1 inverse agonist. Phase I studies are planned to begin in 2019 for treatment of diseases with organ-specific fibrosis.42

Modulation of Alternative Targets

As endocannabinoid system research has advanced, other potential targets have been identified in playing important roles in the system as a whole. TRPV1, as described above, interacts with endocannabinoid receptors and plays a role in the nociceptive pain pathway, thus has garnered interest for drug development. In addition to NEO1940, NeoMed Institute has another candidate, NEO6860, which acts as a selective inhibitor of capsaicin-activated TRPV1 channels (not temperature- or pH-activated channels) and is seeking indications for the treatment of osteoarthritis pain, neuropathic pain, and visceral pain/chronic pancreatitis.43 First generation TRPV1 antagonist programs had previously failed (including AMG517, SB-7054498, and MK2295) mainly due to their non-selective modes of channel antagonism, leading to the serious adverse effects of hyperthermia and impaired noxious heat sensation.44-46 In phase I trials, NEO6860 has shown to yield analgesic effects without affecting body temperature or sensitivity to heat.47-51

Another research focus has been FABP5, an endocannabinoid interacting protein. A product developed by Artelo that inhibits FABP5, ART26.12,9 is undergoing lead identification studies to create a compound with optimum design for potential indications of cancer and pain-related conditions.40

Modulation of Catabolism

Given that AEA and 2-AG are primarily metabolized via FAAH and MAGL, respectively, it was originally thought that inhibition of either enzyme could allow for increased levels of both to elicit beneficial effects. There were multiple FAAH selective inhibitors developed and pursued for different pain conditions throughout the 21st century, including BIA10-2474, PF-04457845, JNJ-42165279, SSR-411298, V-158866, and URB597. However, none made it past Phase II clinical trials due to lack of efficacy or due to causing acute and rapidly progressive neurological syndrome.52-55 There were two postulated reasons related to selective inhibition of FAAH for which these pipeline products failed. One was that increasing synaptic concentrations of AEA allowed for increased activity on both CB1 receptors (desired effect) and TRPV1 channels (involved in nociception), thus overall analgesia was limited.17,18 The other was blocking the FAAH metabolic pathway allowed for a higher percentage of AEA to metabolize via COX-2 into prostaglandins, leading to an increased pro-inflammatory effect.17

Notably, only one MAGL selective inhibitor has made it to clinical trials. Phase II trials have begun for ABX-1431, developed by Abide Therapeutics for treatment of Tourette Syndrome and pain, and phase 1 trials showed it to be well tolerated and to elicit positive impacts on Tourette Syndrome symptoms.56-58

Endocannabinoid Target Product Candidates

The ultimate failure of selective FAAH inhibitors, as well as the complexity of the endocannabinoid system, has led to growing interest and research into products that have multiple targets within this system. One product, OMDM-198, is a dual inhibitor of FAAH and TRPV1 and has shown efficacy in terms of reduction of osteoarthritic pain in rat models, however, it is unclear whether these will progress to human trials.17,59,60 A different dual inhibitor of FAAH and COX-2, ARN2508, has shown to increase plasma AEA levels and decrease prostaglandin and thromboxane A2 levels after IV administration.61,62 Similarly, there are no current human clinical trials of this compound in progress, therefore its ultimate place in therapy has yet to be determined. Table II provides additional detail on the above products.


The knowledge and information available on cannabinoid compounds and the endocannabinoid system is ever-expanding as research progresses and becomes more focused. Although there are several areas of potential therapeutic development of products acting on the endocannabinoid system designed to treat pain and non-pain related conditions, it is pertinent to acknowledge that the overall place in therapy for almost all of these products (pharmaceutical, botanical, or otherwise) is still widely unknown and sound clinical data in these areas is still lacking. Likewise, it is also important to consider that the majority of these products (especially those acting on CB1 and CB2 receptors) may be associated with cognitive dysfunction and increases in psychoactive behavior, thus should always be used with caution.27,63

Editor's Note: See also Mark A. Ware, MBBS, and David J Casarett, MD, discuss key considerations in prescribing cannabis for pain care.

The overall viability and optimization of medications acting on the endocannabinoid system is still difficult to discern from current research; however, past and continued progress shows hope in finding greater uses of cannabinoid products.

Last updated on: May 6, 2019
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