Cannabinoids in the management of difficult to treat pain.
- GW Pharmaceuticals Vashon, WA, USA.
This article reviews recent research on cannabinoid analgesia via the endocannabinoid system and non-receptor mechanisms, as well as randomized clinical trials employing cannabinoids in pain treatment. Tetrahydrocannabinol (THC, Marinol((R))) and nabilone (Cesamet((R))) are currently approved in the United States and other countries, but not for pain indications. Other synthetic cannabinoids, such as ajulemic acid, are in development. Crude herbal cannabis remains illegal in most jurisdictions but is also under investigation. Sativex((R)), a cannabis derived oromucosal spray containing equal proportions of THC (partial CB(1) receptor agonist ) and cannabidiol (CBD, a non-euphoriant, anti-inflammatory analgesic with CB(1) receptor antagonist and endocannabinoid modulating effects) was approved in Canada in 2005 for treatment of central neuropathic pain in multiple sclerosis, and in 2007 for intractable cancer pain. Numerous randomized clinical trials have demonstrated safety and efficacy for Sativex in central and peripheral neuropathic pain, rheumatoid arthritis and cancer pain. An Investigational New Drug application to conduct advanced clinical trials for cancer pain was approved by the US FDA in January 2006. Cannabinoid analgesics have generally been well tolerated in clinical trials with acceptable adverse event profiles. Their adjunctive addition to the pharmacological armamentarium for treatment of pain shows great promise.
As many as one in five Americans lives with chronic pain. Many of these people suffer from neuropathic pain (nerve-related pain) — a condition that is associated with numerous diseases, including diabetes, cancer, multiple sclerosis, and HIV. In most cases, the use of standard analgesic medications such as opiates and NSAIDS (non-steroidal anti-inflammatory drugs) is ineffective at relieving neuropathic pain. Further, long-term use of most conventional pain relievers, including acetaminophen, opioids, and NSAIDs, is associated with a host of potential adverse side effects, including dependence, heart-attack, liver damage, and accidental overdose death.
Survey data indicates that the use of cannabis is common among patients with chronic pain and patients who use it for this indication typically report it to be an effective treatment. Majorities further report that cannabis possesses fewer side effects than conventional pain medications and that it provides greater symptom management than opioids.
In addition to these anecdotal claims, numerous clinical trials report that inhaled marijuana alleviates neuropathic pain. A recent review identifies 35 controlled studies specific to the use of cannabis or cannabinoids in pain treatment, involving over 2,000 subjects. These include a pair of randomized, placebo-controlled clinical trials demonstrating that smoking cannabis reduces neuropathy in patients with HIV by more than 30 percent compared to placebo.[6-7] (Additional details on these studies appear in the HIV section of this publication.) A University of California at San Diego double-blind, placebo-controlled trial reported that inhaled cannabis significantly reduced capsaicin-induced pain in healthy volunteers. A University of California at Davis double-blind, randomized clinical trial reported both high and low doses of inhaled cannabis reduced neuropathic pain of diverse causes in subjects unresponsive to standard pain therapies. A McGill University study reported that smoked cannabis significantly improved measures of pain, sleep quality and anxiety in participants with refractory pain for which conventional therapies had failed. Another clinical trial reported that both inhaled cannabis and oral THC significantly decreased pain sensitivity and increased pain tolerance in healthy subjects exposed to experimental painful stimuli.
Clinical trials also report that vaporized cannabis is effective at mitigating pain. A 2013 FDA-approved trial assessing the impact of vaporized cannabis on neuropathic pain reported that even low doses of THC (1.29 percent) “provided statistically significant 30% reductions in pain intensity when compared to placebo.” A 2014 Israeli open-label clinical trial reported that the administration of a single dose of whole-plant cannabis via a thermal-metered inhaler was effective and well tolerated among patients suffering from nerve pain. Placebo-controlled data published in 2015 in The Journal of Pain further reported that vaporized cannabis provides “a dose-dependent reduction in diabetic peripheral neuropathy pain in patients with treatment-refractory pain.” A 2016 placebo-controlled trial in a cohort of 42 subjects with spinal injury neuropathy reported that vaporizing cannabis with low to moderate levels of THC elicited a “significant analgesic response” in study participants.
A review of these and other trials published in the British Journal of Clinical Pharmacology concluded, “[I]t is reasonable to consider cannabinoids as a treatment option for the management of chronic neuropathic pain with evidence of efficacy in other types of chronic pain such as fibromyalgia and rheumatoid arthritis as well.” A separate review published in The Clinical Journal of Pain further concluded, “Overall, based on the existing clinical trials database, cannabinergic pain medicines have been shown to be modestly effective and safe treatments in patients with a variety of chronic pain conditions. … Incorporating cannabinergic medicine topics into pain medicine education seems warranted and continuing clinical research and empiric treatment trials are appropriate.” Another review of the data similarly reports, “[C]annabinoids are safe [and] demonstrate a modest analgesic effect and provide a reasonable treatment option for treatment chronic non-cancer pain.” Most recently, a review of over 10,000 scientific studies by the National Academies of Sciences, Engineering, and Medicine concluded that whole-plant cannabis is effective for the treatment of chronic pain in adults. “In adults with chronic pain, patients who were treated with cannabis or cannabinoids are more likely to experience a clinically significant reduction in pain symptoms,” they determined.
Longitudinal trials have also shown cannabis therapy to be safe and effective for pain treatment. A one-year assessment of Canadian chronic pain patients reported that daily use of herbal cannabis was associated with sufficient safety and efficacy. Compared to controls, patients in the cannabis use group experienced a significant reduction in average pain intensity while reporting no increased risk of adverse cognitive or pulmonary events. Authors concluded: “[T]his study suggests that the adverse effects of medical cannabis are modest and comparable quantitatively and qualitatively to prescription cannabinoids. The results suggest that cannabis at average doses of 2.5g/d in current cannabis users may be safe as part of carefully monitored pain management program when conventional treatments have been considered medically inappropriate or inadequate.”
Preclinical data indicates that cannabinoids, when administered in concert with one another, are more effective at ameliorating neuropathic pain than the use of a single agent — a phenomenon sometimes referred to as the entourage effect. Investigators at the University of Milan have reported that the administration of single cannabinoids such as THC or CBD produce limited relief compared to the administration of plant extracts containing multiple cannabinoids, terpenes (oils), and flavonoids (pigments). Researchers concluded: “[T]he use of a standardized extract of Cannabis sativa … evoked a total relief of thermal hyperalgesia, in an experimental model of neuropathic pain, … ameliorating the effect of single cannabinoids.” … “Collectively, these findings strongly support the idea that the combination of cannabinoid and non-cannabinoid compounds, as present in [plant-derived] extracts, provide significant advantages in the relief of neuropathic pain compared with pure cannabinoids alone.” Other studies have reported similar results.
Cannabis dosing also permits some chronic pain patients to significantly reduce their use of opioids. A 2011 clinical trial assessing the administration of vaporized plant cannabis in chronic pain patients on a daily regimen of morphine or oxycodone reported that inhaled “cannabis augments the analgesic effect of opioids.” Authors concluded, “The combination (of opioids and cannabinoids) may allow for opioid treatment at lower doses with fewer side effects.” A 2016 Israeli clinical trial of intractable pain patients similarly reported that inhaled cannabis reduced symptom severity and also was associated with 44 percent overall reduction in subjects’ use of opiates. A separate University of Michigan study of 244 chronic pain subjects similarly reported that cannabis use led to a 64 percent decrease in opioid consumption. Patient survey data published in 2017 reported that 97 percent of respondents “strongly agreed/agreed” that they are able to decrease the amount of opioids they consume when they also use cannabis.”
In jurisdictions that permit medical cannabis access, patients are using fewer opioids. According to the findings of a 2015 National Bureau of Economic Research study, “[S]tates permitting medical marijuana dispensaries experience a relative decrease in both opioid addictions and opioid overdose deaths compared to states that do not. The NBER findings are similar to those published in 2014 in the Journal of the American Medical Association (JAMA) Internal Medicine which also reported that the enactment of statewide medicinal marijuana laws is associated with a 24.8 percent lower mean annual opioid overdose mortality rate compared with states without medical cannabis laws. A 2016 study produced by Castlight Health similarly reports that rates of unauthorized opiate use is significantly lower in medical cannabis jurisdictions. Incidences of opioid-related hospitalizations and traffic-related fatalities have also fallen, as have overall prescription drug spending. (For a comprehensive summary of relevant studies finding that legal cannabis access is associated with decreases in opioid use, abuse, hospitalization, and mortality, please see NORML’s fact-sheet, Relationship Between Marijuana and Opioids.) Consequently, some pain experts are now advising that physicians recommend cannabis therapy in addition to or in lieu of opiate medications to “reduce the morbidity and mortality rates associated with prescription pain medications.”
Role of Cannabinoids in Pain Management
Ethan B. Russo and Andrea G. Hohmann
Key Points Cannabinoids are pharmacological agents of endog-• enous (endocannabinoids), botanical (phytocannabinoids), or synthetic origin. Cannabinoids alleviate pain through a variety of • receptor and non-receptor mechanisms including direct analgesic and anti-inﬂ a mmatory effects, modulatory actions on neurotransmitters, and interactions with endogenous and administered opioids. Cannabinoid agents are currently available in various • countries for pain treatment, and even cannabinoids of botanical origin may be approvable by FDA, although this is distinctly unlikely for smoked cannabis.
An impressive body of literature supports cannabinoid • analgesia, and recently, this has been supplemented by an increasing number of phase I–III clinical trials.
Plants and Pain
I t is a curious fact that we owe a great deal of our insight into pharmacological treatment of pain to the plant world [ 1 ] . Willow bark from Salix spp. led to development of aspirin and eventual elucidation of the analgesic effects of prostaglandins
and their role in inﬂ a mmation. The opium poppy ( Papaver somniferum ) provided the prototypic narcotic analgesic morphine, the ﬁ rst alkaloid discovered, and stimulated the much later discovery of the endorphin and enkephalin systems. Similarly, the pharmacological properties of cannabis ( Cannabis sativa ) prompted the isolation of D 9- tetrahydrocannabinol (THC), the major psychoactive ingredient in cannabis, in 1964 [ 2 ] . It is this breakthrough that subsequently prompted the more recent discovery of the body’s own cannabis-like system, the endocannabinoid system (ECS), which modulates pain under physiological conditions. Pro-nociceptive mechanisms of the endovanilloid system were similarly revealed by phytochemistry of capsaicin, the pungent ingredient in hot chile peppers ( Capsicum annuum etc.), which activates transient receptor potential vanilloid receptor-1 (TRPV1). Additional plant products such as the mints and mustards activate other TRP channels to produce their physiological effects.
The Endocannabinoid System
There are three recognized types of cannabinoids: (1) the phytocannabinoids [ 3] derived from the cannabis plant, (2) synthetic cannabinoids (e.g., ajulemic acid, nabilone, CP55940, WIN55, 212-2) based upon the chemical structure of THC or other ligands which bind cannabinoid receptors, and (3) the endogenous cannabinoids or endocannabinoids. Endocannabinoids are natural chemicals such as anandamide (AEA) and 2-arachidonoylglycerol (2-AG) found in animals whose basic functions are “relax, eat, sleep, forget, and protect” [ 4 ] . The endocannabinoid system encompasses the endocannabinoids themselves, their biosynthetic and catabolic enzymes, and their corresponding receptors [ 5 ] . AEA is hydrolyzed by the enzyme fatty-acid amide hydrolase (FAAH) into breakdown products arachidonic acid and ethanolamine [ 6] . By contrast, 2-AG is hydrolyzed primarily by the enzyme monoacylglycerol lipase (MGL) into breakdown products arachidonic acid and glycerol [ 7 ] and to a lesser extent by the enzymes ABHD6 and ABHD12. FAAH, a postsynaptic enzyme, may control anandamide levels near sites of synthesis, whereas MGL, a presynaptic enzyme [ 8 ] , may terminate 2-AG signaling following CB 1 receptor activation. These enzymes also represent therapeutic targets because inhibition of endocannabinoid deactivation will increase levels of endocannabinoids at sites with ongoing synthesis and release [ 9 ] . The pathways controlling formation of AEA remain poorly understood. However, 2-AG is believed to be formed from membrane phospholipid precursors through the sequential activation of two distinct enzymes, phospholipase C and diacylglycerol lipase- a . First, PLC catalyzes formation of the 2-AG precursor diacylglycerol (DAG) from membrane phosphoinositides. Then, DAG is hydrolyzed by the enzyme diacylglycerol lipase- a (DGL- a ) to generate 2-AG [ 199 ]
Fig. 18.1 Putative mechanism of endocannabinoid-mediated retrograde signaling in the nervous system. Activation of metabotropic glutamate receptors ( mGluR) by glutamate triggers the activation of the phospholipase C ( PLC) -diacylglycerol lipase ( DGL) pathway to generate the endocannabinoid 2-arachidonoylglycerol ( 2-AG ). First, the 2-AG precursor diacylglycerol ( DAG ) is formed from PLC-mediated hydrolysis of membrane phospholipid precursors ( PIPx ). DAG is then hydrolyzed by the enzyme DGL- a to generate 2-AG. 2-AG is released from the postsynaptic neuron and acts as a retrograde signaling m olecule. Endocannabinoids activate presynaptic CB 1 receptors which reside on terminals of glutamatergic and GABAergic neurons. Activation of CB 1 by 2-AG, anandamide, or exogenous cannabinoids (e.g., tetrahydrocannabinol, THC ) inhibits calcium in ﬂ ux in the presynaptic terminal, thereby inhibiting release of the primary neurotransmitter
(i.e., glutamate or GABA) from the synaptic vesicle. Endocannabinoids are then rapidly deactivated by transport into cells (via a putative endocannabinoid transporter) followed by intracellular hydrolysis. 2-AG is metabolized by the enzyme monoacylglycerol lipase ( MGL ), whereas anandamide is metabolized by a distinct enzyme, fatty-acid amide hydrolase ( FAAH ). Note that MGL co-localizes with CB 1 in the presynaptic terminal, whereas FAAH is localized to postsynaptic sites. The existence of an endocannabinoid transporter remains controversial. Pharmacological inhibitors of either endocannabinoid deactivation (e.g., FAAH and MGL inhibitors) or transport (i.e., uptake inhibitors) have been developed to exploit the therapeutic potential of the endocannabinoid signaling system in the treatment of pain (Figure by authors with kind assistance of James Brodie, GW Pharmaceuticals)