Cannabis-based medicines for chronic neuropathic pain in adults (Review)
In a recent Cochrane meta-analysis of studies investigating the use of medical cannabis for chronic neuropathic pain management, the authors determined that no results were what they could consider “high quality.” All data which related to degrees of pain relief, adverse events, and “Patient Global Impression of Change” were largely of very low or low quality, with some outcomes being of moderate quality. The meta-analysis concluded that no existing evidence backs up the use of cannabis for chronic neuropathic pain; however, the quality of evidence examined highlights the need for more controlled studies.
Dr. Caplan and the #MDTake:
Depending on the system of organization one prefers, pain can be divided up into different subtypes. For one system, it’s three subtypes: neuropathic, nociceptive, and “other.” For another system, pain can be organized by timing (sharp, acute, chronic, breakthrough), location (bone, soft tissue, nerve, referred, phantom), or by the relative system (emotional, cancer, body.) This review discusses the subtype category of “neuropathic pain” as a means of grouping pain to study. The measures used to assess the pain are as subjective as the categories themselves. Clearly, compounding the two subjective divisions is unlikely to produce “high quality” data, but it is a misleading interpretation to take away that there is no good quality information to glean from the observations this review organizes, and also a misinterpretation to jump to an idea that cannabis is not helpful. Rather, given the statistical tools we currently use, and the subjective systems of understanding pain are not well-matched to translating the effects of cannabis on pain into this type of data.
Cannabis Use in Individuals with Spinal Cord Injury or Moderate to Severe Traumatic Brain Injury in Colorado
Spinal cord injury patients report that medical cannabis helped them alleviate many symptoms of their injury including spasticity, pain, sleepdisruptions, stress, and anxiety. Traumatic brain injury patients list their reason for use as reducing stress/anxiety and improving sleep. Both groups of patients reported recreational use prior to and following injury for a variety of reasons.
Dr. Caplan and the #MDTake:
Healing from traumatic injuries is never solely a matter of local tissue changes. The injured tissues, and the experience of being injured create ripple effects which can disrupt multiple other organ systems, and the entire experience of normalcy. A chemical stress response is one of the most common (and often adaptive) responses to an injury, but the burden of stress, adapting to a new illness, and associated loss of normalcy and sleep can be disastrous to the process of healing. As anxiety and sleeplessness snowball into daily problems themselves, a kernel of injury sometimes amplifies to become a life-altering change.
In a recent review of systematic reviews and controlled studies, researchers were unable to find sufficient evidence to support the clinical use of medical cannabis or the pharmaceutical formulations for gastrointestinal, cancer, or rheumatic pain, or weight loss in cancer of AIDS. Many data from previous studies were either statistically insignificant or were of low quality. However, the authors did find that existing literature sufficiently supported the treatment of neuropathic pain with cannabis. Additional controlled studies may shed more light on the use of cannabis for general pain management. Interestingly, while the authors do raise two important limitations of the studies that they highlight in the article (inadequate size of some studies and generally limited supply of traditional scientific studies from which to draw conclusions) they do not address some of the more fundamental concerns with the reporting.
Dr. Caplan and the #MDTake:
The limitations of studies in cannabis are numerous and an important consideration for researchers as they study cannabis, and equally essentially to consider for those of us reading the study product. To my personal count, there are at least 40 different types of biases that can skew data in a way that delivers information other than a precise description of actual events. This study, as many like it, presumptuously assumes that, if data doesn’t show a trend that so-mocked “anecdotal” data shows, then surely the anecdote must be incorrect. What if the reviews are simply not yet accurately recording what human iteration has discovered repeatedly for millennia?
The conclusion the review draws follows:
“Conclusion: The public perception of the efficacy, tolerability, and safety of cannabis-based medicines in pain management and palliative medicine con- flicts with the findings of systematic reviews and prospective observational studies conducted according to the standards of evidence-based medicine.“
Is the right question for science to question the validity of the stories that individuals are telling, against an imperfect science of information collection, as well as the limited scope of statistical validity for understanding data? Or is the right task for science to question its own methods of assumptions in discovery and understanding?
On the one hand, we have millions of people calling the color of the ocean “blue.” On the other hand, we have data that tells us that water, in fact, has no color. Similarly, the anecdotes from cannabis consumers are telling a story that is starkly different from the currently available data.
For those interested in combing through a close inspection of the many ways that data can be misrepresented and misunderstood, check out https://first10em.com/bias/
Cannabinoid receptor 2: Potential role in immunomodulation and neuroinflammation Review
Previous research and characterization of cannabinoid receptors (CBs) have consistently demonstrated the therapeutic potential for many medical conditions. CB1, the receptor responsible for the intoxicating (and other psychoactive) effects of cannabis, has demonstrated the ability to modulate concentrations of certain other neurotransmitters, giving it the capability of acting as an antidepressant. Additionally, mice lacking CB1 receptors exhibited increased neurodegeneration, increased susceptibility for autoimmune encephalomyelitis, and inferior recovery to some traumatic nerve injuries. The CB2 receptor is generally attributed to support for modulating the immune system and calming some of the body’s natural, core inflammatory signaling systems. Activation of the receptor has been found to associate with neuroinflammatory conditions in the brain, and in appropriate circumstances, can result in the programming of cell death among some immune cells. This effect points toward a role in communication, inflammation and autoimmune diseases. Furthermore, evidence points to CB2 holding significant potential in HIV therapy. Binding partners of CB2 inhibit the HIV-1 infection and help to diminish HIV replication. Historically, these staggering findings have escaped traditional modern medical understanding. Further investigation into the therapeutic potential of cannabis, with respect to the treatment of inflammation, depression, autoimmune diseases, and HIV is at a minimum, clearly warranted for a more comprehensive understanding of effective medical therapy.
Dr Caplan and the #MDTake:
The main points here no longer seem to be investigational trends, but just pillars of Cannabis Medicine that are embarrassingly new, and poorly recognized by the modern medical establishment. While the bulk of consumers, including patients, may not engage with the science on a molecular basis, by iterative or intuitive science, individuals are diligently discovering what forms of cannabis serve their personal interests more effectively. This is, through a scientific lens, a trial-and-error adventure through products, which have various ratios of cannabinoid-receptor activation or inhibition, that ultimately achieves a similar result, which is a clinical relief for a particular ailment. Does the fact that the process does not begin with a clear understanding of the involved receptors and receptor modulators really matter? If one of the primary objectives of Medicine is to treat and/or ease suffering, and the products are built upon a bedrock of chemical safety (misuse, inappropriate, or misinformed production of products notwithstanding), it should not matter that people discover it by happy accident, or through more direct achievement.
Crossing the Line: Care of a Pediatric Patient with Intractable Seizures and Severe Neuropathic Pain in Absence of Access to Medical Marijuana
A recent case report discussing a six-year-old patient suffering from a seizure disorder has exposed the difficulty is receiving treatment across state lines. The patient was prescribed medical marijuana that alleviated the severity and duration of her seizures but was weaned off of that medication when traveling to Nebraska for a therapeutic surgery, due to the legal status in the state. This case study exposes the difficulty of treating patients across the country due to the legal variability of cannabis across states.
Author’s summary reflections:
“The current state-specific approach to medical marijuana notably burdens patients, families, and health care systems with a fragmented approach to symptom management based on local context. The stigmatization or legal implications of medical marijuana in certain settings may lead well-meaning providers to avoid asking about use or to struggle with appropriate response. Provider response to parents reporting medical marijuana use in Schedule I settings notably varies from direct inquiry, feigned ignorance, or informed ignoring. Ideally, providers would compassionately and competently inquire about pharmaceutical and nonpharmaceutical interventions (to include medical marijuana use) as part of comprehensive palliative care symptom assessments.”
“Pancreatic cancer is particularly refractory to modern therapies, with a 5-year survival rate for patients at a dismal 8%. One of the significant barriers to effective treatment is the immunosuppressive pancreatic tumor microenvironment and development of resistance to treatment. New treatment options to increase both the survival and quality of life of patients are urgently needed. This study reports on a new non-cannabinoid, non-psychoactive derivative of cannabis, termed FBL-03G, with the potential to treat pancreatic cancer. In vitro results show major increase in apoptosis and consequential decrease in survival for two pancreatic cancer models- Panc-02 and KPC pancreatic cancer cells treated with varying concentrations of FBL-03G and radiotherapy. Meanwhile, in vivo results demonstrate therapeutic efficacy in delaying both local and metastatic tumor progression in animal models with pancreatic cancer when using FBL-03G sustainably delivered from smart radiotherapy biomaterials. Repeated experiments also showed significant (P < 0.0001) increase in survival for animals with pancreatic cancer compared to control cohorts. The findings demonstrate the potential for this new cannabis derivative in the treatment of both localized and advanced pancreatic cancer, providing impetus for further studies toward clinical translation.
“From the results of this study, the key findings include, observation that a non-cannabinoid derivative of cannabis can enhance radiotherapy treatment outcomes in-vitro and in-vivo as highlighted in Figures 2, 4. Secondly, the sustained delivery of the cannabis derivative FBL-03G from smart radiotherapy biomaterials (SRBs) results in tumor growth inhibition of both locally treated and distant untreated tumors, with and without radiotherapy. The use of smart radiotherapy biomaterials (SRBs) (8, 23) was recently proposed as a novel approach to deliver cannabinoids, allowing for prolonged exposure of tumor cells to these cannabis derivatives, which is expected to be more effective (10). The FBL-03G payload used in this study is a flavonoid non- cannabinoid derivative of cannabis, and the potential to inhibit both local and metastatic tumor progression is remarkable, especially for pancreatic cancer, with a dismal 5-year survival rate of 8% (1).”
“While the results indicate that sustained exposure of tumor cells to FBL-03G can boost both local and metastatic tumor cell kill, the mechanism of such action needs to be further investigated. One hypothesis is that, FBL-03G can serve as an immunotherapy agent, inhibiting growth of locally treated and untreated tumors, representing metastasis. Metastasis accounts for most of all cancer-associated suffering and death, and questionably presents the most daunting challenge in cancer management. Henceforth, the observed significant increase in survival is promising, especially for pancreatic cancer which is often recalcitrant to treatments. Another hypothesis is that sustained delivery allows FBL-03G to reach the untreated tumor over a prolonged period as well. Either way, the FBL-03G results reveal a new potential non-cannabinoid cannabis derivative with major potential for consideration in further investigations in the treatment of pancreatic cancer, where new therapy options are urgently needed.”
Dr Caplan’s Take:
This article is one in a growing collection of impressive data that highlights a critical area of Medicine that has hidden from the scientific community for decades. The goal of the review is NOT to hail praise on cannabis as a panacea, nor even a sole treatment option, for pancreatic cancer. Rather, it highlights that it seems to be working effectively, both in living tumor cells in the lab and in animal models with live tumor cells. For a devastating illness that currently carries a grim prognosis, the proposition here is to learn more.
The milestones between pioneering scientific study and effective medication are many and there is much work to be done. Studies must be reviewed, criticized, replicated, integrated, before pioneering products can be developed, produced, tested, scaled, brought to market, marketed, sold, and consumed. The process is long, but at least there is a seed of hope at the beginning!
Forget CBD; flavonoids found in cannabis have been found to be 30 times more effective painkillers than aspirin, targeting inflammation at the source and making them great alternatives for pain killers. If produced on a larger scale, they could help get away from the opioid crisis.
Title: Neuroanatomical alterations in people with high and low cannabis dependence
A recent article has been published revealing some volumetric alterations in specific brain regions in people who report dependence on cannabis. Magnetic resonance imaging revealed that the volume of certain regions, including the hippocampus, the cerebellum, and the caudate, in cannabis dependent users, were all reduced in size, relative to recreational cannabis users who did not use cannabis chronically. Future research will likely focus on the effects of the structural alterations on patients’ reward, stress, and addiction-relevant circuitry to examine the possible relevance of cannabis dependance on those circuits.
There are certainly possibilities that suggest this volume difference could be of concern, but there are also a great number of explanations (more than likely) whereby this is related to another variable that we have not yet fully appreciated.
Currently, cannabis use is thought to have a little-to-no risk of addiction (beyond any “normal” product of medical value, such as coffee or eyeglasses), because it does not act directly on the reward circuit. Opioids have a high risk of addiction, and therefore a concerning safety profile, in part because of the direct effect of the opioid system on the reward pathway of the central and peripheral nervous systems. While the endocannabinoid system has been observed to act directly up the reward circuit, it does so in subtle, soft ways, making it an ideal adjunct therapy for opioids to help with pain management. Current research provides inconsistent results and appropriately emphasizes a need for more testing to validate the possibility of cannabis as a recommended pain medication.
A recent letter to the editor exposes the large discrepancy between the number of registered medical marijuana patients and those who self-reported medical cannabis use. Estimates given by the National Survey on Drug Use and Health (NSDUH) suggest that 2.5% of Americans over the age of 12 used medical cannabis in 2013-2015 but a study from 2016 found that only 641,176 people were licensed to receive medical cannabis, a prevalence of 0.4%. If the numbers published by the NSDUH are accurate then states may need to delve into how so many people are accessing medical cannabis without proper licensing in order to better regulate the supply. If the numbers are extrapolated to 2019 and include all states where medical cannabis use in legal then more than 6.2 million people should be licensed but may not be.
Medical cannabis can be difficult to acquire due to its cost, post-legalization. Although medical cannabis in Massachusetts is readily available with a large number of dispensaries across the state, the cost of obtaining a doctor’s recommendation, complying with state fees, and then paying for the cannabis at a dispensary can be too much for some patients. Although MA will soon be waving the state fee, to obtaining a license, clinicians are still expensive and without the support of the federal government allowing national insurance companies to cover medical cannabis the costs still add up quickly. Fortunately, some dispensaries are designed to cater to those who need financial support.