Medical cannabis or cannabinoids for chronic non-cancer and cancer related pain: a systematic review and meta-analysis of randomised clinical trials
BMJ 2021; 374 doi: https://doi.org/10.1136/bmj.n1034 (Published 09 September 2021) Cite this as: BMJ 2021;374:n1034Linked Practice
Medical cannabis or cannabinoids for chronic pain: a clinical practice guideline
Linked Editorial
Medical cannabis for chronic pain
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Dear Editor
Dr. Moore and colleagues question why our review did not acknowledge the work by IASP. Our literature search was conducted up to January 2021, at which time the IASP review had not yet been published.
The IASP review concluded that the effect of medical cannabis on pain relief was supported by only low, or very low certainty evidence due to risk of bias; however, they were unable to conduct subgroup analyses to confirm if risk of bias had been realized as they rated most risk of bias criterion among eligible trials as ‘unclear’. We used a modified Cochrane risk of bias instrument that avoids unclear ratings, [1] which allowed us to conduct subgroup analyses comparing high vs. low risk of bias on each item. We found no evidence of credible subgroup effects and, accordingly, we did not rate down the certainty of evidence for risk of bias.
The IASP review found, as did we, that effects of cannabis and cannabinoids on chronic pain were small. Specifically, we found a modelled risk difference for achieving the minimally important difference in pain relief (or greater) of 10%. However, we conducted a systematic review of patients’ values and preferences that found many people living with chronic pain place high value on the possibility of small but important improvement in pain relief. [2] Our guideline panel, which also included 3 patient partners living with chronic pain in addition to pain experts and front-line clinicians, considered this information when interpreting effect estimates. Given the close balance between modest benefits and modest risk of harms, the guideline panel made a weak recommendation to offer a trial of non-inhaled medical cannabis to people living with chronic pain for whom treatment without cannabis had proven insufficient.[3] A weak recommendation means that not all informed patients will make the same decision, and that healthcare providers should engage in shared decision-making to help patients arrive at a decision that is accountable to their context and consistent with their values and preferences.
Moore and colleagues note that some important adverse events are not captured in randomized trials, and thus not reflected in our review. We agree, which is why we conducted a separate systematic review of observational studies to inform long-term and infrequent harms associated medical cannabis and cannabinoids for chronic pain.[4] These findings were carefully considered by our guideline panel.
Other differences between the IASP review and ours include the following:
- We only considered trials with at least 1 month follow-up, as we believe that trials of chronic pain should inform tolerability of therapy in the longer term, and because outcomes such as quality of life and functional gains require sufficient time to manifest among treatment responders. The IASP considered any duration of follow-up, and so included 10 trials of cannabis for chronic pain with less than 1-month follow-up; five trials followed patients for only 1-day after treatment.
- The IASP review stratified effects by type of cannabis or cannabinoid, which greatly limited their ability to conduct meta-analyses. We pooled treatment effects across different types of cannabis and cannabinoids as subgroup analyses did not find credible evidence of subgroup effects.
- The IASP review only explored the proportion of treatment responders (e.g., 30% pain relief) when this information was directly reported by trials; most studies did not and were thus excluded from these analyses. We complemented our presentation of average effects by modelling the proportion of responders using data from all eligible trials – an approach that has been endorsed by the OMERACT working group.[5]
Jason W. Busse
Li Wang
Thomas Agoritsas
1. Akl EA, Sun X, Busse JW, et al. Specific instructions for estimating unclearly reported blinding status in randomized trials were reliable and valid. J Clin Epidemiol. 2012; 65(3): 262-7.
2. Zeng L, Lytvyn L, Wang X, et al. Values and preferences towards medical cannabis among people living with chronic pain: a mixed-methods systematic review. BMJ Open 2021;11:e050831. doi:10.1136/bmjopen-2021-050831
3. Busse JW, Vankrunkelsven P, Heen AF, et al. Medical cannabis for chronic pain: a clinical practice guideline. BMJ 2021; 374: n2040 (http://dx.doi.org/10.1136/bmj.n2040)
4. Zeraatkar D, Cooper MA, Agarwal A , et al. Long-term and infrequent harms of medical cannabis for chronic pain: A systematic review of observational studies. Preprint available at: https://medrxiv.org/cgi/content/short/2021.05.27.21257921v1
5. Busse JW, Bartlett SJ, Dougados M, et al. Optimal strategies for reporting pain in clinical trials and systematic reviews: recommendations from an OMERACT 12 workshop. J Rheumatol. 2015;42(10):1962-1970. doi:10.3899/jrheum.141440
Competing interests: No competing interests
Dear Editor
It is understandable that the BMJ should seek to inform its readers about cannabis in pain management, given the very large number of people with untreated chronic pain [1], together with the massive growth in a new market claiming pain relief with cannabis-based products – with projections of compounded 20% market growth to over $16 billion by 2027 in the USA alone. [2]
The BMJ systematic review of cannabinoids for cancer and chronic non-cancer pain [3] starts with the premise that a new systematic review is needed because limitations of analytical approaches and interpretation of findings produced conflicting results previously. It oddly does not point out that an overview of 57 previous self-declared systematic reviews investigated just this point in substantial detail [4; posted online in May 2020]: reviews with industry links are typically of low quality and quite positive about effects of cannabinoids for pain, while Cochrane reviews tend to be much more conservative.
That overview was part of a major investigation by the International Association for the Study of Pain (IASP) task force comprehensively examining preclinical, clinical, and epidemiological evidence for the benefits and harms of cannabinoids, cannabis, and cannabis-based medicine for pain. The IASP position statement concludes that “Due to the lack of high-quality clinical evidence IASP does not currently endorse general use of cannabis and cannabinoids for pain relief”. [5]
For efficacy, the IASP investigation included a new comprehensive systematic review of randomised, double-blind trials of all cannabinoids, at all doses, in all types of pain, using not only standard risk of bias but also others critical in the assessment of pain trials [6; posted online in August 2020]. The IASP efficacy review differs (inter alia) from the Wang review in the GRADE-ing of evidence (low or very low certainty, rather than moderate or high certainty), which meant that there was little confidence in the estimates of any effect. Any estimates of efficacy were perforce based on studies with uncertain and high risk of bias, and any effect size was small. It is also critical to acknowledge that some important adverse effects encountered in real-world clinical settings are not necessarily captured in clinical trials [7] - an issue not emphasized by the Wang review.
It was disappointing that the Wang review omitted any discussion of the many differences with the systematic review produced by IASP. It is a disservice to readers and people living with pain that authors, peer-reviewers, and editors did not address the major differences in conclusions between the BMJ and IASP approaches.
For cannabinoids and pain, we are faced with major differences in opinion between the series of articles in the BMJ, and the IASP endorsed task force. These differences come down to interpretation of what the evidence concludes and the standards used to assess that evidence. As task force authors we are clearly biased by our many decades of working in pain and evidence. It is interesting that results of three new randomised trials published in 2021 are profoundly negative, finding no analgesic effects for cannabidiol in acute low back pain [8] or hand osteoarthritis or psoriatic arthritis [9], or cannabidivarin for HIV-associated neuropathic pain [10]. Only one trial found some benefit for THC-enriched cannabis oil – in eight fibromyalgia patients in Brazil [11].
There is a perfect storm ahead when the growth of the cannabis market meets the overwhelming desire of patients for treatments. What patients deserve most are evidence-supported treatments. We need to be very careful with the claims made about both efficacy and harm, appling the highest possible standards of research integrity and scholarship. After all, chronic pain patients have been failed before; we are still dealing with the fallout of market driven expansion in opioid use, overclaiming, and the failures in both science and regulation to offer rational and evidence-based options [12].
Perhaps the responsible BMJ editorial position is to let readers know about the thorough investigation by IASP, and its finding that: “IASP does not currently endorse general use of cannabis and cannabinoids for pain relief”. [4]
Andrew Moore
Retired researcher into (inter alia) pain and evidence
Plymouth, United Kingdom.
COI: personal payment for advice to Biogen Inc on design of future neuropathic pain trials
Emma Fisher
Department for Health Centre for Pain Research, University of Bath, Bath, United Kingdom.
COI: E fisher reports grants from vs Arthritis and NIHR outside the submitted work.
Christopher Eccleston
Professor, Department for Health Centre for Pain Research, University of Bath, Bath, United Kingdom; Cochrane Pain, Palliative, and Supportive Care Review Groups, Oxford University Hospitals, Oxford, United Kingdom; Department of Clinical and Health Psychology, Ghent University, Ghent, Belgium.
COI: C. Eccleston reports grants from vs Arthritis, MayDay Foundation, Cochrane, and NIHR outside the submitted work.
Simon Haroutounian
Associate Professor and Chief of Clinical Pain Research in the Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO, USA.
COI: In the past 36 months Simon Haroutounian has received research funding from the US National Institutes of Health, US Department of Defense, and Disarm Therapeutics. SH has received personal fees from Vertex Pharmaceuticals, Medoc Ltd, and Rafa Laboratories.
Ian Gilron
Director of Clinical Pain Research, Research Committee Chair, Professor of Anesthesiology & Perioperative Medicine, Biomedical & Molecular Sciences, Centre for Neuroscience Studies, and School of Policy Studies, Queen’s University Kingston Health Sciences Centre, 76 Stuart Street, Vic 2 Pavillion, Kingston, Ontario, CANADA
COI: I. Gilron reports personal fees from GW Research, Adynxx, Biogen, Eupraxia, Novaremed and Teva.
Andrew RC Rice
Professor of Pain Research, Imperial College London, Chelsea and Westminster Hospital Campus, 369 Fulham Road, London SW10 9NH
COI: Andrew SC Rice interests occurring in last 24 months:
• Employee of Imperial College London and Hon. Consultant in Pain Medicine, Chelsea and Westminster Hospital NHS Foundation Trust
• Councillor International Association Study of Pain and Chair of Presidential Taskforce on Cannabis and Cannabinoid Analgesia
• ASCR undertakes consultancy and advisory board work for Imperial College Consultants - in the last 24 months this has included remunerated work for: Confo, Vertex, Orion, Shanghai SIMR Biotech, Asahi Kasei, & Theranexis
• ASCR was the owner of share options in Spinifex Pharmaceuticals from which personal benefit accrued upon the acquisition of Spinifex by Novartis in July 2015. The final payment was made in 2019.
• ASCR is named as an inventor on patents: Rice A.S.C., Vandevoorde S. and Lambert D.M Methods using N-(2-propenyl)hexadecanamide and related amides to relieve pain. WO 2005/079771; Okuse K. et al Methods of treating pain by inhibition of vgf activity EP13702262.0/ WO2013 110945
• Advisor British National Formulary
• Member Joint Committee on Vaccine and Immunisation- varicella sub-committee
• Analgesic Clinical Trial Translation: Innovations, Opportunities, and Networks (ACTTION) steering committee member
• Non Freezing Cold Injury Independent Senior Advisory Committee (NISAC): Member
• Medicines and Healthcare products Regulatory Agency (MHRA), Commission on Human Medicines - Neurology, Pain & Psychiatry Expert Advisory Group
References
1. Rice ASC, Smith BH, Blyth FM. Pain and the global burden of disease. Pain. 2016 Apr;157(4):791-796. doi: 10.1097/j.pain.0000000000000454. PMID: 26670465.
2. U.S. Cannabinoids Market Size, Share & Trends Analysis Report By Product (Cannabidiol (CBD), Tetrahydrocannabinol (THC), Cannabinol (CBN), Cannabidiolic Acid (CBDa)), And Segment Forecasts, 2020 – 2027. Grand View Research (https://www.grandviewresearch.com/industry-analysis/us-cannabinoids-market) accessed Sept 15 2021.
3. Wang L, Hong PJ, May C, Rehman Y, Oparin Y, Hong CJ, Hong BY, AminiLari M, Gallo L, Kaushal A, Craigie S, Couban RJ, Kum E, Shanthanna H, Price I, Upadhye S, Ware MA, Campbell F, Buchbinder R, Agoritsas T, Busse JW. Medical cannabis or cannabinoids for chronic non-cancer and cancer related pain: a systematic review and meta-analysis of randomised clinical trials. BMJ. 2021 Sep 8;374:n1034. doi: 10.1136/bmj.n1034. PMID: 34497047.
4. Moore RA, Fisher E, Finn DP, Finnerup NB, Gilron I, Haroutounian S, Krane E, Rice ASC, Rowbotham M, Wallace M, Eccleston C. Cannabinoids, cannabis, and cannabis-based medicines for pain management: an overview of systematic reviews. Pain. 2021 Jul 1;162(Suppl 1):S67-S79. doi: 10.1097/j.pain.0000000000001941. PMID: 32804833.
5. IASP Presidential Task Force on Cannabis and Cannabinoid Analgesia International Association for the Study of Pain Presidential Task Force on Cannabis and Cannabinoid Analgesia position statement, PAIN: July 2021: Volume 162 - Issue - p S1-S2 doi: 10.1097/j.pain.0000000000002265
6. Fisher E, Moore RA, Fogarty AE, Finn DP, Finnerup NB, Gilron I, Haroutounian S, Krane E, Rice ASC, Rowbotham M, Wallace M, Eccleston C. Cannabinoids, cannabis, and cannabis-based medicine for pain management: a systematic review of randomised controlled trials. Pain. 2021 Jul 1;162(Suppl 1):S45-S66. doi: 10.1097/j.pain.0000000000001929. PMID: 32804836.
7. Mohiuddin M, Blyth FM, Degenhardt L, Di Forti M, Eccleston C, Haroutounian S, Moore A, Rice ASC, Wallace M, Park R, Gilron I. General risks of harm with cannabinoids, cannabis, and cannabis-based medicine possibly relevant to patients receiving these for pain management: an overview of systematic reviews. Pain. 2021 Jul 1;162(Suppl 1):S80-S96. doi: 10.1097/j.pain.0000000000002000. PMID: 32941319.
8. Bebee B, Taylor DM, Bourke E, Pollack K, Foster L, Ching M, Wong A. The CANBACK trial: a randomised, controlled clinical trial of oral cannabidiol for people presenting to the emergency department with acute low back pain. Med J Aust. 2021 May;214(8):370-375. doi: 10.5694/mja2.51014. Epub 2021 Apr 12. PMID: 33846971.
9. Vela J, Dreyer L, Petersen KK, Lars AN, Duch KS, Kristensen S. Cannabidiol treatment in hand osteoarthritis and psoriatic arthritis: a randomized, double-blind placebo-controlled trial. Pain. 2021 Aug 27. doi: 10.1097/j.pain.0000000000002466. Epub ahead of print. PMID: 34510141.
10. Eibach L, Scheffel S, Cardebring M, Lettau M, Özgür Celik M, Morguet A, Roehle R, Stein C. Cannabidivarin for HIV-Associated Neuropathic Pain: A Randomized, Blinded, Controlled Clinical Trial. Clin Pharmacol Ther. 2021 Apr;109(4):1055-1062. doi: 10.1002/cpt.2016. Epub 2020 Sep 6. PMID: 32770831.
11. Chaves C, Bittencourt PCT, Pelegrini A. Ingestion of a THC-Rich Cannabis Oil in People with Fibromyalgia: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial. Pain Med. 2020 Oct 1;21(10):2212-2218. doi: 10.1093/pm/pnaa303. PMID: 33118602; PMCID: PMC7593796.
12. Bell RF, Kalso EA. Cannabinoids for pain or profit? Pain. 2021 Jul 1;162(Suppl 1):S125-S126. doi: 10.1097/j.pain.0000000000001930. PMID: 32804834.
Competing interests: All authors were members of an IASP Task force on cannabis, cannabinoids, and cannabis-based medicines for treatment of pain RAM: None EF: grants from vs Arthritis and NIHR outside the submitted work CE: grants from vs Arthritis, MayDay Foundation, Cochrane, and NIHR outside the submitted work. SH: In the past 36 months Simon Haroutounian has received research funding from the US National Institutes of Health, US Department of Defense, and Disarm Therapeutics. SH has received personal fees from Vertex Pharmaceuticals, Medoc Ltd, and Rafa Laboratories. IG: personal fees from GW Research, Adynxx, Biogen, Eupraxia, Novaremed and Teva. AR: • Employee of Imperial College London and Hon. Consultant in Pain Medicine, Chelsea and Westminster Hospital NHS Foundation Trust • Councillor International Association Study of Pain and Chair of Presidential Taskforce on Cannabis and Cannabinoid Analgesia • ASCR undertakes consultancy and advisory board work for Imperial College Consultants - in the last 24 months this has included remunerated work for: Confo, Vertex, Orion, Shanghai SIMR Biotech, Asahi Kasei, & Theranexis • ASCR was the owner of share options in Spinifex Pharmaceuticals from which personal benefit accrued upon the acquisition of Spinifex by Novartis in July 2015. The final payment was made in 2019. • ASCR is named as an inventor on patents: Rice A.S.C., Vandevoorde S. and Lambert D.M Methods using N-(2-propenyl)hexadecanamide and related amides to relieve pain. WO 2005/079771; Okuse K. et al Methods of treating pain by inhibition of vgf activity EP13702262.0/ WO2013 110945 • Advisor British National Formulary • Member Joint Committee on Vaccine and Immunisation- varicella sub-committee • Analgesic Clinical Trial Translation: Innovations, Opportunities, and Networks (ACTTION) steering committee member • Non Freezing Cold Injury Independent Senior Advisory Committee (NISAC): Member • Medicines and Healthcare products Regulatory Agency (MHRA), Commission on Human Medicines - Neurology, Pain & Psychiatry Expert Advisory Group
Dear Editor
It is with great eagerness that I read this systematic review and meta-analysis of randomised clinical trials evaluating the effectiveness of medical cannabis and cannabinoids for chronic pain.
I would like to comment that given chronic pain can lead to significant disability, the exclusion of those receiving disability benefits from the research remains problematic. The same can be said for the exclusion of those with comorbid mental illness. Surely those most severely affected by chronic pain are indeed also likely to suffer from concurrent psychosocial related impacts and consequently more inclined to consider alternative therapy? Thus, to properly identify the true impact of medical cannabis on the target population, we must also seek to include adult patients living with significant disability and mental illness correlated with chronic pain in this topical discussion.
Furthermore, the authors of the article mentioned that their results were based on studies that followed 1 to 5.5 months of treatment. They go on to state that according to their meta-analysis, there is little improvement in both emotional and social functioning in those patients using medical cannabis and cannabinoids. Upon further scrutiny of these results, it is evident that the trials assessing emotional functioning and social functioning only followed the cohort for 3.5 to 4 months. In light of this, I would like to add that positive increments in emotional and social functioning typically take longer and follow the enhancement of pain control and physical health.
Therefore, it is vital we encourage further research assessing long term therapeutic benefits of medical cannabis in order to ascertain a more accurate view of how patients are affected. Going forward, any large-scale analysis commenting on social and emotional benefit of medical cannabis should underline the brevity of treatment and view results within this context.
Competing interests: No competing interests
Re: Medical cannabis or cannabinoids for chronic non-cancer and cancer related pain: a systematic review and meta-analysis of randomised clinical trials
Dear Editor
We were very interested in the role of cannabinoids for chronic non-cancer and cancer related pain. We work with patients that experience debilitating chronic pain and it is a question that is raised from time to time by both patients and family, which is why we carefully read the review published by Wang in BMJ [1]
This systematic review not only focuses on cancer and non-cancer related pain as the main objective, but also other outcomes (e.g., physical functioning, sleep quality, emotional role, etc.) concluding in a very broad research question.
All of the RCTs analyzed for cancer-related pain had very significant losses (up to 27%), making the final results questionable. In addition, in 3 of 4 trials the generation of random sequence was not reported, leading to lack of allocation concealment. In both cases, this led to downgrade to moderate certainty on GRADE analysis due to a high risk of bias. We argue it would be more appropriate to downgrade two levels from certainty to a low certainty level for cancer related pain.
The results for cancer-related pain were not statistically significant WMD -0.10 (-0.28 to 0.09); and for non-cancer pain they only reached slight statistical significance WMD -0.63 (-0.96 to 0.29). In two systematic reviews [2] [3] evaluating minimum clinically important differences (MCID) in both acute and chronic pain, MCID is closer to 2 cm on a 10 cm scale, not 1 cm as reported by this systematic review, and appears to be dependent on the level of baseline pain. Thus, we argue that the results are not statistically significant nor clinically relevant in cancer pain, and not clinically relevant in chronic non-cancer pain.
The follow-up time of the studies for cancer-related pain was very short (35 days), and although follow-up for chronic non-cancer pain was longer (up to 3 months), we reckon it is insufficient to determine adverse effects and the trials were unpowered to detect them.
Almost all of the trials included (29 of 33) used placebo as comparison instead of standard treatment, which further illustrates the little effect of cannabinoids on pain. In addition, cannabinoids proved to have several side effects, namely transient cognitive impairment, vomiting, drowsiness, impaired attention, and nausea, in addition to dizziness which was notable. Subgroup analysis for dizziness was higher RR 1.95 (1.50 to 2.55) for less than 3 months and RR 4.65 (3.30 to 6.55) for more than 3 months follow-up. We would also like to point out that side effects related to mental health were not taken into consideration, nor the potential long-term risk for developing psychosis later in life.
Therefore, due to the lack of clinically relevant effectiveness, short follow-up time, and risk of adverse events, we conclude there is currently not enough evidence to use cannabinoids in the management of chronic pain.
[1] Wang, L., Hong, P. J., May, C., Rehman, Y.(2021). Medical cannabis or cannabinoids for chronic non-cancer and cancer related pain: a systematic review and meta-analysis of randomised clinical trials. BMJ (Clinical research ed.), 374, n1034. https://doi.org/10.1136/bmj.n1034
[2] Olsen, M. F., Bjerre, E., Hansen, M. D. (2017). Pain relief that matters to patients: systematic review of empirical studies assessing the minimum clinically important difference in acute pain. BMC Medicine, 15(1), 35. https://doi.org/10.1186/s12916-016-0775-3
[3] Frahm Olsen, M., Bjerre, E., Hansen, M. D. (2018). Minimum clinically important differences in chronic pain vary considerably by baseline pain and methodological factors: systematic review of empirical studies. Journal of Clinical Epidemiology, 101, 87–106.e2. doi:10.1016/j.jclinepi.2018.05.0
Competing interests: No competing interests