Accurate Education - Marijuana (Cannabis): Chronic Pain Overview

Marijuana (Cannabis):

Chronic Pain Overview

The use of marijuana (cannabis) for chronic pain remains highly controversial and lacks good quality evidence regarding the specifics of clinical effectiveness and the details of treatment including dosing frequency, amount and duration. The following information is provided as an introduction to uses of cannabis and cannabis-based products for chronic pain based on current research.

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Marijuana (Cannabis): Chronic Pain

Pain is the most common reason individuals seek health care and the most common reason people turn to marijuana (cannabis) and cannabis-based products for therapeutic beneifits. It has an estimated incidence in the United States higher than that of diabetes, cancer, and heart disease combined. Chronic pain can be complex and can result from different mechanisms. While there are different categories of pain, the two dominant categories are nociceptive and neuropathic pain. Nociceptive pain is the nervous system’s response to injury, often perceived as a localized dull, aching or throbbing pain. Neuropathic pain involves the nerves and can result from changes in the nervous system exposed to chronic pain, independent of real tissue damage. Neuropathic pain is often experienced as sharp, burning or electric in nature, sometimes starting in one location and referred to another adjacent or distant location.

The Endocannabinoid System (ECS

Cannabis (marijuana) and cannabis-based products interact with cannabinoid receptors in the endocannabinoid system to modulate pain and reduce inflammation. Briefly, the endocannabinoid system (ECS) is distributed throughout the central and peripheral nervous system and is intimately involved in inflammation and pain processing. It also plays important regulatory roles with virtually every organ system.

The components of the ECS include three cannabinoid receptors: CB1, CB2 and a presumed third cannabinoid receptor, GPR55, sometimes termed CB3. The ECS manufactures “ligands,” which interact with these three receptors, referred to as “endogenous cannabinoids” (cannabinoids made in the bod by the ECS vs. “exogenous cannabinoids” made outside the body, including the marijuana cannabinoids (phytocannabinoids, from plants).

The two primary endocannabinoid ligands are anandamide (AEA), and 2-arachidonoylglycerol (2-AG) and they interact at the CB1 and CB2 receptors with variable affinities and actions. The CB1 receptors are the most abundant receptors in the brain and some of the most abundant in both the peripheral and central nervous system. CB1 receptors are found extensively in anatomical pain pathways and can modulate pain pathways involving opioid, serotonin, and NMDA receptors as well as other indirect mechanisms.

The CB2 receptors are located primarily in peripheral tissues (internal organs, muscles and skin) and immune cells where they impact inflammation through the release of inflammatory chemicals (cytokines and chemokines), and migration of inflammatory immune cells (neutrophils and macrophages). CB2 receptors are also present in the central nervous system where they also contribute to pain relief via different mechanisms including modulation of dopamine release.

Through interactions with the cannabinoid receptors in these pain pathways either directly or indirectly, both endogenous and phyto-cannabinoids (i.e. THC, CBD) can reduce sensitization of pain sensory pathways and induce alterations in cognitive (emotions and thought) processing in chronic pain states. By altering cognitive processing, cannabinoids can reduce both the severity and the impact of pain as well as enhance the ability to cope with and adapt to the presence of pain.

See: The Endocannabinoid System (ECS)

See below for a more in-depth review of cannabis, the ECS and neuropathic pain

There is a great deal of interest in the potential therapeutic benefits of cannabis and there is substantial evidence that it is an effective treatment for chronic pain in adults, especially neuropathic pain. That being said, when evaluating evidence to guide a clinician’s approach to the use of cannabis and/or its constituents, one is confronted with a complex array of studies that ultimately fail to provide a very specific pathway for treatment recommendations. In an effort to base therapeutic recommendations on meaningful evidence it should be noted that evidence-based medicine (EBM) has three components: (1) clincial research evidence, (2) the physician’s experience, and (3) the patient’s experience. In order to reach a clinical decision in the management of an individual case, all three components are relevant. That being said, anecdotal medical experience and personal advocacy should not supercede evidence based on high-quality research when it is available.

Clincal research including systematic reviews and meta-analyses of such research, although part of the evidence, is not the entirety of EBM. However, being that we are in the early history of the clinical application of cannabis and/or its constituents and we are still lacking adequate documentation of both clinician and patient-based experience, it is necessary to rely on the current research available to guide recommendations for therapeutic uses of cannabis and/or its constituents.

Before embarking on a review of the current research regarding the use of “medical marijuana” for chronic pain, it is important to remember that pain is defined as:

“An unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage.”

As such, the management of pain includes attention to chronic stress and emotional states, including anxiety and depression. Cannabinoids, the most abundant compounds found in cannabis, are known to facilitate reductions not only in pain but also in chronic stress reactions and emotional learning—important components in chronic pain.

Marijuana constituents and the management of chronic pain

To understand the application of cannabis and cannabis-based products in the management of chronic pain, it is necessary to understand that cannabis, the plant, contains many pharmacologically active constituents, likely 100 or more, that might contribute to the analgesic benefits of cannabis. The two primary compounds found in cannabis, the cannabinoids delta-9-tetrahydrocannabinol (Δ-9THC) and cannabidiol (CBD), appear likely responsible for much of cannabis’s pharmacologic effects, especially the analgesic effects. However, other constituents also contribute to the analgesic effects of cannabis, although their roles are not well defined or understood. These other constituents include other cannabinoids and terpenes, such as caryophyllene and myrcene, as well as other compounds.

Furthermore, different plants contain different amounts and ratios of these pharmacologically active constituents and therefore each plant offers different analgesic benefits. Most studies of “medical marijuana” are based on the use of different strains of cannabis, either smoked, vaped or ingested, in which little or nothing is known about the amounts or ratios of the constituents in the cannabis/cannabis products studied. At best, the relative amounts of Δ-9THC and CBD may be known but rarely is the terpene profile identified in most available studies.

This fact is very important when, as in the case of Louisiana, “medical marijuana” products include gel caps or tinctures with specific amounts and ratios of THC & CBD but otherwise unknown amounts and ratios of the terpenes or other constituents. Additionally, trying to apply conclusions based on studies of plants or other cannabis-based products different from those available in LA is problematic, making it impossible to accurately predict specific analgesic or other clinical benefits of LA cannabis-based products. Out of necessity it is mostly a trial and error process in the use of LA products for pain or other conditions.

See: Selecting Flower Products & Strains for Pain

THC and CBD

The two main variables in the use of cannabis-based products are the total amounts and the relative ratios of the THC and CBD in the products. The ratio of the two is important because THC and CBD interact with one another in ways that determine the clinical effects, although the exact mechanisms of this interaction remains unknown. Patients using marijuana for pain relief most commonly report that the most effective cannabis strains often have an equal balance of THC and CBD.

THC contributes to the analgesic, anti-spasmodic, anti-tremor, anti-inflammatory, appetite stimulant, sleep and anti-nausea properties of cannabis. THC is 20 times more anti-inflammatory than aspirin and twice as anti-inflammatory as hydrocortisone. Importantly, THC and its active metabolite, 11-Hydroxy-THC. also produce the “high” or euphoria associated with use of cannabis as well as other side effects such as anxiety.

CBD, however, reduces pain and anxiety and enhance sleep but does not produce any mind-altering “high” or euphoric effects. CBD also has anti-inflammatory benefits as well as anti-convulsant, anti-psychotic, antioxidant, neuroprotective and immunomodulatory effects. CBD modulates some of the effects of THC, including reducing THC-induced anxiety.

For more detailed information about THC and CBD, please see:

THC, CBD & the Endocannabinoid System.

The Current State of Research Investigating Use of Cannabis for Treatment of Chronic Pain

The following sections provide a review on what is currently known or believed regarding the use of cannabis and cannabis-derived constituents in the management of chronic pain. The sections are broken down by which cannabis or cannabis-based products have been studied. To begin, the first section offers a review of what has been published as systematic reviews of both cannabis and cannabis-based products related to chronic pain.

Cannabis & Pain: Systematic Reviews

A “systematic review” is a review of pertinent scientific literature using systematic methods to collect research data, critically appraise the quality of the research studies, and synthesize conclusions about the specific outcomes being measured. They are designed to provide a complete, exhaustive summary of current evidence relevant to a research question. Review authors pool numerical data about the effects of treatments through a process called meta-analyses which assess the evidence for any benefits or harms from the treatments. In this way, systematic reviews summarize the existing clinical research on a topic.

In the case of systematic reviews evaluating cannabis and cannabis-based products and their effectiveness for chronic pain, the conclusions available are complicated by an extensive mix of cannabis-based products studied. Many studies evaluate smoked camnabis plants with no definitive measure of the constituents in the plants and no definitive means of measuring actual dosing of these constituents. Other studies evaluate specific cannabis-based prescription drugs including Casemet (nabilone), a synthetic cannabinoid similar to but different from THC, Marinol (dronabinol), a synthetic THC and Sativex (nabiximols), a cannabis plant-based extract containing THC, CBD and other cannabinoids. While these studies are helpful, they do not provide definitive evidence to guide conclusions regarding effectiveness or dosing of other different cannabis-based products such as those available in Louisiana.

These systematic reviews do, however, provide evidence that at least 0n some level, cannabis-based products have the potential for analgesic benefit. A number of systematic reviews have been published in the last few years, especially since 2017.

In “Cannabinoids for medical use – a systematic review and meta-analysis. – 2015,” published in 2015 in the Journal of the American Medical Association, it was concluded that “there is moderate-quality evidence to support the use of cannabinoids for the treatment of chronic pain.”

In an article published in 2017, “Cannabis and Pain – A Clinical Review – 2017,” the authors also concluded that there is modest evidence supporting the use of cannabinoids for pain. Furthermore, they noted that there is initial evidence for the use of “medical cannabis” to allow for a possible reduction in the use of opioids for pain.”

A systematic review of systematic reviews of randomized controlled trials (RCT) and prospective long-term observational studies of the use of cannabinoids in pain management and palliative medicine was published in 2017: “Cannabinoids in Pain Management and Palliative Medicine.” An RCT is defined as “a study design that randomly assigns participants into an experimental group or a control group. As the study is conducted, the only expected difference between the control and experimental groups in an RCT is the outcome variable being studied.” In this case, the outcome variable is the cannabis product being studied. Randomized controlled trials are considered the only reliable method for establishing evidence for effective therapy and are the highest standard of research.

This 2017 study reviewed pertinent publications from 2009 to 2017 including 750 publications identified but only 11 SRs met their inclusion criteria; 3 of them were of high and 8 of moderate methodological quality. 2 prospective long-term observational studies with medical cannabis and 1 with tetrahydro- cannabinol/cannabidiol spray (THC/CBD spray) were also analyzed. According to evidence-based medicine criteria, the reviewers concluded that there is limited evidence for a benefit of THC/CBD spray in the treatment of neuropathic pain to support the use of THC/CBD spray in carefully selected neuropathic pain patients who have shown insufficient response to standard pharmacotherapy.

They further concluded that the use of all cannabinoids for any indication in pain management should be regarded as an individual therapeutic trial due to inadequate evidence for any benefit of cannabinoids (dronabinol, nabilone, medical cannabis, or THC/CBD spray) to treat cancer pain or pain of rheumatic or gastrointestinal origin. It was also noted that treatment with cannabis-based medicines is associated with central nervous and psychiatric side effects.

A subsequent systematic review was published in 2018 that evaluated only randomized controlled trials (RCTs), “Cannabinoids for the Treatment of Chronic Pain – A Critical Review of Randomized Controlled Trials – 2018.” This review evaluated 21 trials involving a total of 1614 adult participants with chronic pain including the following conditions: chronic back pain, chronic headaches, temporomandibular disorder, fibromyalgia, myofascial pain, neuropathic pain, HIV neuropathy, rheumatoid arthritis, and osteoarthritis. The duration of the selected trials were rather short, ranging from 5 days to 6 weeks. The types of cannabinoids studied included smoked cannabis, THC, cannabidiol (CBD), Sativex (nabiximol) and synthetic cannabinoids (e.g., dronabinol, nabilone) at different doses and routes of use.

All but one of the 21 trials concluded that cannabinoids are effective in managing chronic pain, especially, neuropathic pain. However, while various pain intensity scales were used to assess the effectiveness for pain, other relevant outcomes were often ignored. While 13 studies did evaluate other outcomes such as sleep, mood, anxiety, and depression, physical function and quality of life, the results for these outcomes were not clearly reported or absent. Only 7 trials reported improvements in sleep and only 5 trials reported improvements in quality of life. While 3 trials reported improvements in all measured outcomes. the variability in outcome measures in the studies made it very diffcult to evaluate and to conclude the overall effectiveness of cannabinoids for chronic pain. Unfortunately, the authors concluded that while there remains an inadequate number of of high-quality trials to allow for consistent guidelines or recommendations for clinical practice, cannabinoids can be a potential treatment for chronic pain.

“Systematic review of systematic reviews for medical cannabinoids“ is another study published in 2018 that evaluated 1085 articles and identified 23 for pain. Their meta-analysis of 15 RCTs found that 39% of patients taking cannabinoids attained at least a 30% pain reduction, with most studies evaluating nerve pain. However, sensitivity analysis found study size and duration affected findings, with larger and longer RCTs finding no benefit. The systematic reviews focusing on pain reduction in rheumatologic pain and fibromyalgia generally found equivocal results or insufficient evidence for benefit, respectively. (For additional systematic reviews, see References below).

A recent systematic review published in 2018 evaluated cannabis and cannabis-based products specifically looking at their benefit in neuropathic (nerve) pain: Cannabis-based medicines for chronic neuropathic pain in adults (Review). This Cochrane review evaluated 16 studies with 1750 participants. The studies were 2 to 26 weeks long and compared an oromucosal spray with a plant-derived combination of THC and CBD (10 studies), a synthetic cannabinoid mimicking THC (nabilone) (two studies), inhaled herbal cannabis (two studies) and plant-derived THC (dronabinol) (two studies) against placebo (15 studies) and an analgesic (dihydrocodeine) (one study). As with the others, the authors concluded there is a lack of good evidence that any cannabis-derived product is effective for any chronic neuropathic pain. Existing evidence remains weak.

A 2021 systematic review, “Cannabinoids, cannabis, and cannabis-based medicine for pain management – a systematic review of randomised controlled trials,“concluded “Studies in this field have unclear or high risk of bias, and outcomes had GRADE rating of low- or very low-quality evidence. We have little confidence in the estimates of effect. The evidence neither supports nor refutes claims of efficacy and safety for cannabinoids, cannabis, or CBM in the management of pain.”

“Cannabis and Cannabinoids for the Treatment of People With Chronic Noncancer Pain Conditions“, a systematic review and meta-analysis of controlled and observational studies, published 2018 also concluded that the evidence on the effectiveness of cannabinoids for chronic noncancer pain conditions (CNCP) is limited, largely based on the quality of the research published. Several reasons were cited for the limitations. First, sample sizes are mostly small and risk of bias are significant so caution should be taken when interpreting their outcomes and applying their findings to the population at whole.

Second, since most studies are of limited duration (median of 8 weeks) the appropriateness of applying their findings to long-term use of cannabinoids in CNCP is questionable. Studies suggested that reductions in pain intensity were largest for the short term studies, and smaller or nonsignificant in studies of 13-week duration or longer, suggesting that cannabinoids may lose their effectiveness over time. Of additional importance, cannabinoid dose was often poorly recorded in the studies.

Finally, the overall conclusion is that benefit from cannabinoids for pain are relatively small and side effects are significant, although studies indicate most side effects are not serious. Additionally, most of the higher-quality evidence was for neuropathic pain and multiple sclerosis-related pain, with little, low-quality evidence for fibromyalgia or visceral pain, and very few studies evaluating the most common CNCP conditions, such as back and neck problems, migraines, and arthritis.

Of special note: the greatest amount of high-quality evidence was for nabiximols (Sativex). This is important for Louisiana patients since this product most closely matches one of the cannabis-based products available in this state, the balanced THC:CBD tincture with a 1:1 ratio of 5 mg THC and 5 mg CBD/ml.

See: Sativex, FDA-Approved Cannabis-Based Prescription Medications

Conclusions Based on Systematic Reviews

While the evidence for benefit of cannabis and cannabis-based products for chronic pain remains limited and weak, based on few well-designed studies, there is still expectation of effectiveness for cannabis-based products. The future holds promise and new studies are pending. In LA it will be necessary to proceed with products for which there is very limited experience beyond their contents. With appropriate cautions and careful attention to dosing, it is likely benefits will be more clearly identified as well as a greater understanding of dosing amounts and ratios.

Cannabis & Cannabinoids in the Management of Neuropathic Pain

As the popularity of the use of marijuana for medical benefits as grown, so has the research into the components found in marijuana that provide therapeutic benefits. Unfortunately, due to federal government limitations on marijuana research, the research is still limited, and our understanding of how the components found in marijuana work for pain and other conditions. The compounds that are believed, offer, therapeutic benefits, with cannabis include cannabinoids, terpines and flavonoids as reviewed below.

The Endocannabinoid System (ECS) and Neuropathic Pain

The anatomy and physiology of pain, particularly chronic pain, is known however, to have significant contribution from the endocannabinoid system (ECS) of the human body in a somewhat analogous way of the opioid systems of the human body. Just as the opioid system has opioid-specific cell receptors and endogenous opioids manufactured by the human body, called endorphins, there are also cannabinoid-specific receptors and endogenous cannabinoids manufactured by the human body. Cannabinoids are a family of compounds that are made by plants (phytocannabinoidss) including marijuana’s THC and CBD among others, and those that are manufactured in the human body (endocannabionids).

The main components of endocannabinoid system (ECS) are the cannabinoid receptors CB1 and CB2 , the endocannabinoids anandamide (AEA) and 2-arachidonoylglycerol (2-AG), and the enzymes involved in their metabolism, including fatty acid amino hydrolase (FAAH) and monoacylglycerol lipase (MAGL), that are responsible for breaking down AEA and 2-AG, respectively. The ECS is an on-demand system, meaning it largely produces its components when there is a need for the. and is present throughout the peripheral and central nervous systems, including important regions of pain processing, such as the spinal cord (including the ascending and descending nerve pathways and the dorsal root ganglions (DRGs,) the thalamus, amygdala and periaquaqueductal gray matter (PAG).

The ECS also interfaces with the immune system, particularly cells involved with inflammation, particularly neuro-inflammation, that drive chronic pain. The immune cells that play significant roles in the production and maintenance of pain signalling are glial cells, including astrocytes and microglia, that are found adjacent to nerves in the peripheral nervous system, the spinal cord and the brain. These cells have cannabinoid receptors on them, which makes them responsive to the presence of endocannabinoids (AEA & 2-AG), as well as phytocannabinoids (THC, CBD and BCP and others).

Finally, other important components associated with the ECS and its role in pain are nerve receptors of the transient receptor potential family (TRP). including TRPV1)and TRPM8, which are important n the transmission of pain signals.

The following is a brief overview of the components of the ECS where they may play a role in impacting pain, particularly neuropathic pain.

Nerve cells, astrocytes, and microglial cells have the ECS components, and communicate pain signals through CB1 and CB2 receptors that lead to different outcomes in each cell. Presynaptic neurons expresses CB1, TRPV1, TRPM8, and the endocannabinoid membrane transporter (EMT). These receptors are all targeted by endocannabinoids (AEA and 2-AG) that modify pain signaly by changing the neurotransmitter release flow. Postsynaptic neurons, besides having the same receptors, they also have the enzymes that synthesize the enzymes that manufacture and break down all the elements of the ECS, such as FAAH, MAGL, and other enzymes. Interactions with the ECS that can increase or decrease pain would include stimulation of these different receptors to enhance or decrease pain signaling or by influencing the enzymes that manufacture or degrade the cannabinoids.

Even though the most research has been done on the phytocannabinoids, THC and CBD, several other phytocannabinoids such as cannabidivarin (CBDV), 19 -tetrahydrocannabivarin (THCV) and their acidic forms also may offer therapeutic benefits.

Cannabinoids

THC & THCV

THC acts as CB1 and CB2 agonists, it reduces neurotransmitters release by neurons, especially glutamate and it is also a TRPM8 antagonist and a TRPA1 agonist. Another proposed mechanism of action of THC is to inhibit COX-2, which leads to increased levels of AEA and decreased levels of prostaglandins, resulting in the reduction of pro-inflammatory signaling by glial and other immune cells.

THCV is a CB1 antagonist and TRPV1 agonist.

CBD & CBDV

CBD act as TRPV1 and TRPM8 antagonists. while both CBD and CBDV inhibit the cannabinoid degradation enzymes FAAH and MAGL. CBD also acts on the serotoninergic and glycinergic receptors present in other neurochemical processing systems which are involved in pain processing.

THC with CBD

It is also thought that the combination of CBD and THC synergizes their positive effects and reduces THC side effects. Studies suggest the co- administration of CBD and THC decreases dysphoria, anxiety, panic attacks, and other psychoactive effects of THC.

CBN and CBC

Cannabinol (CBN) acts as a CB2R agonist while cannabichromene (CBC), acts as an inhibitor of cyclooxygenase (COX).

Terpenes & Flavonoids

Terpines and flavonoids are other compounds found in cannabis that offer therapeutic benefits. Terpines include many of the aromatic compounds found in cannabis that impart the particular aroma to marijuana flowers and vapors. Particularly important terpines found in cannabis and other plants are beta-caryophylline (BCP), myrcene, pinene and linalool. (See: BCP and Terpines).

Flavonoids, a group of chemical compounds present in many plants not just Cannabis, can reduce inflammation by decreasing the release of pro-inflammatory cytokines from astrocytes and microglia cells.

Resources:

National Academy of Sciences

The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research

These lay-person websites appear to be good resources for exploring medical marijuana. However, as is the case generally regarding medical applications of marijuana and its constitnuents, there is a huge amount of information that is not based in good science and relies on anecdotal (word-of-mouth) evidences. Reader, beware:

References:

Medical Marijuana – Chronic Pain

Cannabis and Pain – Systematic Reviews

Medical Marijuana, Chronic Pain – Cannabinoids & Agmatine

Medical Marijuana, Chronic Pain – Cannabinoids & Palmitoylethanolamide

Medical Marijuana – Opioids

Medical Marijuana – THC, Oral

Tetrahydrocannabinol Does Not Reduce Pain in Patients With Chronic Abdominal Pain in a Phase 2 Placebo-controlled Study – 2017

Medical Marijuana – Pain

Medical Marijuana – Phantom Limb Pain

Medical Marijuana – Product Evaluation

Medical Marijuana –Misc

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Accurate Education – Marijuana (Cannabis): Chronic Pain Overview