22 Nov 2018 [115] Cannabinoids for Chronic Pain
Canada’s parliament legalized the recreational use of herbal cannabis (marijuana) in October 2018. The well-publicized limitations of clinical research and well-recognized side effects such as cannabis intoxication have not deterred people from seeking out and using herbal cannabis for chronic pain in increasing numbers. This is occurring with or without a physician’s authorization.1 In fact, half of Canadians reporting a medical use of herbal cannabis used it for pain relief.2
Adult patients in Canada still require a physician’s ‘authorization’ to legally access cannabis from a licensed producer of cannabis for medical purposes. Facilitating access to any cannabinoid (pharmaceutical or herbal) by a physician in British Columbia is considered the equivalent of a formal prescription by the College of Physicians and Surgeons of British Columbia.3
A recent communication from Harvard University provides this useful advice for physicians:
“Whether you are pro, neutral, or against medical marijuana, patients are embracing it, and although we don’t have rigorous studies and ‘gold standard’ proof of the benefits and risks of medical marijuana, we need to learn about it, be open-minded, and above all, be non-judgmental. Otherwise, our patients will seek out other, less reliable sources of information; they will continue to use it, they just won’t tell us, and there will be that much less trust and strength in our doctor-patient relationship.”4
This Therapeutics Letter provides a brief overview of pharmaceutical cannabinoids and herbal cannabis and the best available evidence for their use in the management of chronic pain.
Pharmaceutical cannabinoids approved for chronic pain management
Pharmaceutical cannabinoids are manufactured drug products with a consistent content and delivery mechanism. Nabiximols (Sativex) and nabilone (Cesamet, generics) are two pharmaceutical cannabinoids approved by Health Canada to date on the basis of clinical trial submissions. Only nabiximols has an approved indication for chronic pain in two clinical circumstances: neuropathic pain in multiple sclerosis, and advanced cancer pain despite the use of strong opioid therapy.5
Pharmaceutical and herbal cannabinoids not formally approved for chronic pain management
Pharmaceutical cannabinoids and herbal cannabis are used for chronic pain in many clinical settings without formal Health Canada approval and thus represent an off-label use. Unfortunately, bias is pervasive throughout the medical cannabinoid literature, including in randomized controlled trials (RCTs). Even within an RCT study design, major challenges remain in interpreting the findings due to the difficulty in maintaining blinding and the great variability of herbal cannabis products.
Herbal cannabis is a complex mixture of many ingredients. Fortunately, producers are currently required to report on the composition of the major active ingredients, which are pharmacologically very different: delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD). For example, a recent World Health Organization pre-review concluded: “CBD exhibits no effects indicative of any abuse or dependence potential… CBD is generally well tolerated with a good safety profile.”6 THC, on the other hand, is responsible for the intoxicating effects and the potential harms associated with that.
At the present time we are hampered by the lack of experimental evidence about product composition, dose, appropriate outcomes to measure benefit, as well as short and long-term adverse effects and adverse interactions with other drugs. There is a great need for more research. Future trials need to use fixed dose product composition and measure real world benefits and harms over suitably long durations.
Neuropathic pain
Benefits:
Two systematic reviews, a Cochrane review7 published in the Cochrane Database of Systematic Reviews in March 2018 and a systematic review of systematic reviews8 published in the Canadian Family Physician in February 2018, best summarize the available clinical trial evidence. We have selected these two reviews, because they are written by non-conflicted authors and are up-to-date, comprehensive and relevant to the Canadian population. Herbal cannabis has less evidence than pharmaceutical cannabinoids. In the Cochrane review, for example, only two of the 16 studies evaluated herbal cannabis (one was an RCT from Canada9 using a product from a Canadian producer).
The Cochrane review reported that cannabis-based medicines increased the number of people achieving 50% or greater pain relief compared with placebo; number needed to treat (NNT) = 20 (95% CI 11 to 100).7 The Canadian review (15 RCTs) reported that more patients taking cannabinoids attained at least a 30% pain reduction: NNT = 11.8
Harms:
In the Cochrane review7 withdrawals due to adverse effects were increased with cannabis; number needed to harm (NNH) = 25 (16 to 50). In the Canadian review8 adverse effects caused more patients to stop treatment, NNH ranged from 8 to 22. Individual adverse events were very common, including dizziness (NNH = 5), sedation (NNH = 5), confusion (NNH = 15), and dissociation (NNH = 20). “Feeling high” was reported in 35% to 70% of users.
Bottom line from the Cochrane review:
“There is a lack of good evidence that any cannabis-derived product works for any chronic neuropathic pain.” 7
Conclusions
- Health care providers need to be knowledgeable and non-judgmental when informing patients about cannabinoids.
- The complexity of cannabinoids as a therapy makes research particularly difficult.
- At the present time we lack good evidence that any cannabis-derived product works for chronic pain.
- Future trials need to use fixed dose product composition and assess real world benefits and harms over suitably long durations.
The draft of this Therapeutics Letter was submitted for review to 130 experts and primary care physicians in order to correct any inaccuracies and to ensure that the information is concise and relevant to clinicians.
References
- Government of Canada. Cannabis, Licensed Producers, Market Data 2018. September 28, 2018. https://canada.ca/en/health-canada/services/drugs-medication/cannabis/licensed-producers/market-data.html [Accessed 20 Nov 2018]
- Rotermann M, Page MM. Prevalence and correlates of non-medical only compared to self-defined medical and non-medical cannabis use, Canada, 2015. Health Reports. 2018; 29(7):3-13. http://web.a.ebscohost.com/ehost/pdfviewer/pdfviewer?vid=1&sid=c4137e02-1078-437c-bb36-8ff2be008e2c%40sessionmgr4010 [Accessed 20 Nov 2018]
- College of Physicians and Surgeons of British Columbia. Practice Standard. Cannabis for Medical Purposes. 2018. https://cpsbc.ca/files/pdf/PSG-Cannabis-for-Medical-Purposes.pdf [Accessed 20 Nov 2018]
- Grinspoon P. Medical marijuana. Harvard Health Blog [Internet]. 2018. https://www.health.harvard.edu/blog/medical-marijuana-2018011513085 [Accessed 20 Nov 2018]
- GW Pharma Ltd. Product Monograph – Sativex 2012. https://pdf.hres.ca/dpd_pm/00016162.PDF [Accessed 20 Nov 2018]
- World Health Organization. Cannabidiol (CBD) Pre-Review Report. Expert Committee on Drug Dependence 39th Meeting, Geneva, 6-10 November 2017. http://who.int/medicines/access/controlled-substances/5.2_CBD.pdf [Accessed 20 Nov 2018]
- Mucke M, Phillips T, Radbruch L, et al. Cannabis-based medicines for chronic neuropathic pain in adults. Cochrane Database of Systematic Reviews 2018, Issue 3. Art. No.: CD012182. DOI: 10.1002/14651858.CD012182.pub2
- Allan GM, Finley CR, Ton J, et al. Systematic review of systematic reviews for medical cannabinoids: Pain, nausea and vomiting, spasticity, and harms. Can Fam Physician. 2018; 64(2):e78-e94. http://cfp.ca/content/cfp/64/2/e78.full.pdf [Accessed 20 Nov 2018]
- Ware MA, Wang T, Shapiro S, et al. Smoked cannabis for chronic neuropathic pain: a randomized controlled trial. CMAJ Canadian Medical Association Journal. 2010; 182(14):E694-701. DOI: 10.1503/cmaj.091414
TN
Posted at 12:59h, 23 NovemberThere is also not a lot of good evidence for other agents used for chronic or neuropathic pain. However, lots of evidence of major harm. There is also no good evidence for most natural health products and OTCs (think cough suppressants, muscle relaxants), to name a few. However, this is not discussed as much as the lack of evidence for marijuana, which continues the stigma surrounding it. However, it’s this very stigma which has woken us up to thinking about the efficacy and safety of drugs in a more meaningful way. Let’s apply this thinking to everything we prescribe.
I applaud you on the suggestion healthcare professionals not be judgemental. It’s about time.
Colleague from Italy
Posted at 13:08h, 24 NovemberGood article, thanks TI for such a good recap.
As a reply for the colleague, I say: firstly it isn’t stigma that increased the attention and criticism on drugs, it’s EBM; passion for science as a way to get near the truth increased attention. And…. (second hand) collateral effects. Did a little ambroxol made psychotic anyone? Not (yet). Does gabapentin made people psychotic? Not (yet), but it causes sedation. It seems that what you report are on very, very different levels.
Also, if there’s stigma nowadays it is against people that don’t smoke, use drugs, etcetera. And frankly, I think that is why the level of interest on this topic is high, it is because Marijuana is a sociological issue, not a medical problem per se. What is happening instead is that social politics, pro-legalization is pushing in favour of a potential pharmaceutical application to make their claim stronger, not vice versa (which is what happens for drugs: first claim the benefit, then promote use).
For me there is no problem if you or patients like it or use it. We should be honest: at the moment there is a lot of bias and it’s not ready to be used fo treatment outside of a research study.
Marc White
Posted at 08:22h, 26 NovemberAlthough it is true that stigma exists it is important to have a more rigorous full spectrum of quantitative and qualitative research in this area that is arms length to industry. I was previously approached by the marijuana industry for investigating efficacy and effectiveness of marijuana products. There were attempts to interfere with scientific independence in early discussions and I declined to participate. The Therapeutics Initiative is a reliable source on the state of research knowledge on a topic. Not being able to make a positive recommendation based on current evidence – should not be interpreted as bias. However what is needed is to consider what range of research is needed to better answer the question. We also need to broaden the question beyond pain relief and consider other functional outcomes relevant to patients’ well-being including work participation.
Terri Betts
Posted at 12:06h, 03 DecemberThank you to TN and Marc White for the insightful comments.
As a pharmacist, I have seen patients experience worthwhile pain relief and improved function from carefully adjusted medical cannabis for chronic pain. I have also encountered patients who have experienced harms from recreational use, especially regular users admitted to hospital for injuries who have suffered withdrawal and poor post-operative pain control. Medical use, when undertaken with little or no guidance on how to choose products and how to adjust doses, often doesn’t turn out well either, putting the patient at undue risk for adverse effects.
As documented in previous Therapeutics Letters, for most adjunct medications for chronic pain, maybe one in ten patients will experience benefit, and equal numbers will experience harm. Antidepressants, which are one popular option, exhibit a daunting withdrawal syndrome that was also well documented in a Therapeutics Letter. I won’t even get into the controversy over opioids.
What to do with a pharmacological approach where evidence is limited, is documented only in small studies where the products were “all over the map” in terms of content of known active compounds, with a variety of other compounds for which we know little about the benefits or possible harms?
Perhaps it has a role for patients who have tried the standard pharmacological approaches and have experienced no significant benefit and/or intolerable adverse effects. In desperation, we tried this within our family, and CBD oil during the day with a dose of THC at bedtime has been the most effective and best tolerated treatment, after trials of amitriptyline and gabapentin provided no benefit, marked loss of function, and suicidal ideation and paranoia (with amitriptyline).
Avoiding judgment, and considering carefully the strength of the evidence and potential for benefit vs harm for everything we prescribe, is a worthwhile goal. And some patients may benefit from our willingness to think “outside the box.”
Therapeutics Initiative
Posted at 13:05h, 01 MarchCochrane has published a podcast summarizing in 3 and a half minutes the findings of the Cochrane Review cited in this Letter. The podcast can be accessed here: https://www.cochrane.org/news/podcast-cannabis-products-adults-chronic-neuropathic-pain
Bottom line: “Overall, we found no difference between people allocated to take cannabis-based medicines or placebo when we looked at the impact on the clinically relevant outcome of an improvement in pain relief of 50% or greater.”
Also: “In summary, we concluded that the potential benefits of cannabis-based medicines in chronic neuropathic pain were outweighed by their potential harms, although a minority of people with cannabis-based medicines do experience substantial symptom relief without clinically relevant adverse events.”
Therapeutics Initiative
Posted at 18:02h, 24 NovemberThe Drug Assessment Working Group of the Therapeutics Initiative produced a state of the science review at the request of the Insurance Corporation of British Columbia (ICBC) to assist in developing funding policy for insurance claims involving the use of herbal cannabis and pharmaceutical cannabinoids for post injury medical management.
Section 1 of the report provides an overall framework for funding policy for ICBC and a summary of clinical trial evidence, harm and pharmacology. Sections 2 to 4, compiled in larger technical reports include details of clinical trial evidence (Section 2); harm (Section 3) and pharmacology (Section 4).
The research on herbal cannabis intoxication as a cause of motor vehicle accidents, while relevant to and important for ICBC, was out of scope for this review. Go to: https://www.ti.ubc.ca/2019/12/18/cannabis/ to view or download this report.