Chronic Pain as Seen by a Clinic Dedicated to Medical Cannabis – Part 2
Part 1 of this blog post showed some real-world data from the Santé Cannabis observational study and quickly went over chronic pain classification; next came a summary of chronic pain management and the importance of a global treatment, ending with a section on the stigma of chronic pain and pain expression.
This sequel focuses on medical cannabis, from its role regarding opioid substitution to the evidence supporting cannabinoids and features of a cannabis treatment.
OPIOID SUBSTITUTION IN CHRONIC PAIN
Chronic pain treatment generally consists of pharmacologic and non-pharmacologic approaches. In certain cases, pain and other symptoms are not successfully controlled, which can be difficult to manage, and it’s challenging to return to a pain-free state. Several non-opioid analgesics are available, but many have low efficacy, poor tolerability and significant adverse effects.  Opioids are widely prescribed to relieve chronic non-cancer pain,  but their prolonged use is problematic due to their addictive potential, the development of tolerance, the hyperalgesia they can induce and their adverse effects. 
The ongoing opioid epidemic (and human deaths) is linked to habitual partiality in opioid prescriptions for chronic pain,  and has prompted a search for other analgesic options. Fuelled by public interest, medical cannabis makes a distinguished mark as a new yet centuries old option.
Safety is the keyword in the case for cannabinoid-based medicines substitution for opioids: the predominant cannabinoid in cannabis, delta-9-tetrahydrocannabinol (THC), has a very low toxicity (“absence of mortality”—World Health Organization).  Cannabidiol (CBD), which is gaining in use, has a favourable safety profile as well. [4, 5]
A recent Canadian initiative produced a consensus-based algorithm on the safe introduction of cannabinoid-based medicines and opioids taper in chronic pain patients. According to this algorithm, cannabinoid-based medicines can be considered in patients with chronic pain taking opioids and not reaching treatment goals, having opioid-related adverse effects and/or at risk of opioid-related harm. 
But what about the evidence supporting the use of cannabinoid-based medicines for chronic pain? Contrary to what some politicians and uninformed healthcare professionals may say, there is evidence. The subject of debate should rather be: is there sufficient evidence?
EVIDENCE FOR CANNABINOIDS USE IN PAIN MANAGEMENT
Cannabinoid-based medicines still carry an important stigma in the research and medical fields.
Interpretation of clinical trial results can vary between authors, but the variation is especially high when judging the evidence for cannabinoids’ efficacy. Indeed, depending on reviews, low to substantial evidence support cannabinoid-based treatments use to manage chronic non-cancer pain. [7-19]
This is understandable since chronic non-cancer pain is an umbrella term that combines various pain conditions that have not been studied to the same extent (see Part 1 for pain classification). Also, reviews may obtain different results based on article design, such as inclusion vs. exclusion of non-randomized controlled trials, analysis per condition vs. “chronic pain” as a single condition, analysis per cannabinoid vs. pooled cannabinoids, etc.
However, the fact remains that for some conditions like multiple sclerosis-related neuropathic pain, “the current literature has provided more reliable data for cannabinoids than for any other drugs”. 
The following subsections cover the evidence in chronic neuropathic pain, fibromyalgia, and chronic pain with an inflammatory component – since those are common pain types seen at our clinic.
CHRONIC NEUROPATHIC PAIN
Chronic neuropathic pain is the best studied type of pain in clinical trials assessing cannabinoids and medical cannabis, [10, 19] with at least 23 published randomized controlled trials (RCTs). [21-46]
The level and quality of the evidence is highly impacted by the quality of trials (questionable blinding to the treatment, small sample size, short trial duration, etc.). Despite the contribution of numerous trials, the evidence that cannabinoids and medical cannabis are effective in chronic neuropathic pain is limited or modest, depending on authors. [9-11, 15, 17, 47]
The following table summarizes study results and shows the supporting evidence for pain reduction with cannabinoid-based medicines (in chronic neuropathic pain), with a modest effect size.
A group of pain specialists and psychiatrists, researchers, and patient representatives compared 12 pharmacological treatments (including THC-rich, CBD-rich and THC:CBD 1:1 treatments) for the management of chronic neuropathic pain. In agreement with several reviews, cannabinoids (especially CBD) scored modestly in pain relief rates as compared to other medications (such as duloxetine, gabapentin, pregabalin, amitriptyline).  However, cannabinoids scored higher than all other medications when combining benefits and safety scores, with the benefits on quality-of-life contributing heavily to the cannabinoids scores. 
Fibromyalgia is being more and more investigated in recent years and patients frequently turn to medical cannabis in the hope of getting some relief from their symptoms. [49, 50] Four published RCTs can be found, [51-54] as well as several observational and retrospective studies. [49, 50, 55-63]
- Two RCTs assessed nabilone in fibromyalgia: one found improvement in pain,  while the other found no effect on pain but superior improvement in sleep as compared to amitriptyline. 
- THC-rich cannabis oil decreased pain and improved functionality, mood and fatigue in a small all-female RCT. 
- Medical cannabis (three dried cannabis formulations: THC-rich, THC:CBD in similar ratio and CBD-rich) was also assessed in one RCT. Cannabis with THC:CBD in similar ratio decreased pain significantly and THC-rich cannabis showed an analgesic effect in some measures. CBD-rich cannabis failed to show an analgesic effect. 
CBD’s analgesic effect has yet to be evaluated in RCTs, but data from observational and cross-sectional studies show that fibromyalgia patients using CBD-rich products report improvement in pain, sleep and anxiety.  Patients report similar benefits from medical cannabis. [56-61] Patients also substitute medical cannabis (including CBD-rich products) for medications such as NSAIDs, opioids, gabapentinoids and benzodiazepines [58-61] due to fewer adverse effects and better symptom management. 
CHRONIC PAIN WITH AN INFLAMMATORY COMPONENT
Chronic pain with an inflammatory component can be a characteristic of several chronic conditions, such as rheumatoid arthritis, osteoarthritis, cancer, inflammatory bowel disease, and more. 
Evidence suggests the endocannabinoid system is involved in the response to inflammation and cartilage degradation; patients with rheumatoid arthritis or osteoarthritis (but not healthy controls) present measurable levels of two endocannabinoids (anandamide and 2-Arachidonoylglycerol) in their synovial fluid.  Based on preclinical evidence, cannabinoids possess anti-inflammatory properties and could be useful to treat rheumatic conditions. [66-68]
At this time, only one randomized controlled trial supports cannabinoid-based medicines potential.
- Nabiximols was studied in patients with rheumatoid arthritis and demonstrated significant analgesic effect. 
The review of the evidence about cannabinoids and pain would be incomplete without something about the difference between men and women. Current research frequently lacks sex-related reporting and analysis, but we are motivated to provide the best patient care – and that implies getting informed and promoting this important topic.
EVIDENCE ABOUT SEX-RELATED DIFFERENCES WITH CANNABINOIDS AND PAIN
Since women with chronic pain outnumber men,  and women count for over 60% of Santé Cannabis patients, we need to address the biological difference between women and men and its impact on cannabinoid-mediated analgesia and pain itself. Only a few clinical trials exist on this topic, and they provide initial evidence that women could be more sensitive to cannabis (or THC) than men.
- Women experience the same acute effects as men despite lower THC blood concentrations,  and are more sensitive to a low THC dose (5 mg oral dose) as compared to men. 
- Considering adverse effects, women are more likely to experience greater subjective anxiety or nervousness, restlessness, and racing heart after THC intake as compared to men (oral or inhaled intake, doses ranging from 5 to 25 mg THC, and controlling for weight and blood concentration). 
Furthermore, preclinical evidence indicates hormones (like estrogen ) modulate pain perception, but the evidence is limited and mixed in clinical trials. [75-77] Preclinical evidence also shows that hormones influence the endocannabinoid system, from receptors’ expression to ligands affinity.  More research is greatly needed to better understand these complex interactions and their implication in clinical practice.
In this last section, we teased out practical information from the scientific evidence to clarify some aspects of medical cannabis treatment.
QUESTIONS ABOUT CANNABIS TREATMENT PLANS
Disclaimer: this section is intended to explain the rationale behind some elements of a treatment plan, and is not meant to be a medical counsel nor a guide to self-medication. In all cases, it’s best to discuss your questions regarding medical cannabis with a healthcare professional.
THC OR CBD FOR PAIN RELIEF?
CBD possesses a favourable safety profile  and is often recommended at the beginning of the treatment. [79, 80] This is a prudent choice regarding adverse events, precautions/relative contraindications, and it is easier than starting patients on both THC and CBD products at once.
However, the analgesic (pain relief) effects of CBD have yet to be demonstrated with the same level of evidence that is supporting the modest (but significant) analgesic effects of THC and THC:CBD formulations.  Some patients may respond well to CBD-rich products (and/or to trace amounts of THC in these products),  but others may need more THC to obtain adequate pain relief. 
WHY DO SOME TREATMENTS USE BOTH ORAL PRODUCTS AND DRIED CANNABIS?
Baseline pain-relief treatment with medical cannabis uses oral administration, exploiting the long-lasting effects  and accurate dosing of ingested products.  Administration frequency varies according to pain frequency, from once daily to two or three times a day. 
Inhalation administration can be helpful to quickly relieve breakthrough pain, [79, 80] with its onset of effects within minutes of inhalation [82-84]. Smoking is common but generally thought inadequate to deliver medication; [85, 86] in comparison, dried cannabis vapourization, which does not burn cannabis, is safer and preferred for treatment delivery. [79, 80, 82]
CAN SOMEONE REPLACE OTHER MEDICATIONS WITH MEDICAL CANNABIS?
That depends on the patient and should be done under medical supervision.
Chronic pain patients frequently seek medical cannabis treatment for symptoms not adequately relieved by their current treatment and/or when their current treatment causes intolerable adverse effects. Some patients on a medical cannabis treatment report reducing or stopping other medications,  but this has not been reproduced in controlled clinical trials [88, 89].
Consensus recommendations do not recommend stopping other pain medications before starting a medical cannabis treatment. [6, 80] With appropriate medical monitoring, it’s possible to gradually taper other medications when the pain or function improves, when the medical cannabis treatment is stable, and/or when the patient requires less as-needed medication (like opioids) for pain relief. 
This concludes our short series of chronic pain blog articles that we hope will be useful for our chronic pain patients, caregivers, healthcare professionals and all other interested readers. At Santé Cannabis, we advocate for patients’ right to access medical cannabis, but we are also committed to our patients’ safety – so we are much aware of the limits of the current evidence supporting medical cannabis use. In this light, it’s essential for us to first, share our knowledge on medical cannabis, and second, to correct misconceptions abounding around cannabis.
For this new yet centuries old therapeutic option, do you agree that there is still no evidence whatsoever? Or should the public discourse evolve to be more nuanced and reflect the advances of modern research?
Author: Charlotte Bastin
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.
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