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We appreciate the interest that our commentary on medical cannabis has generated, and agreement of our stance by Dr. Holbrook and Dr. Yu. Similar to Dr. Yu, we note that the CBD “wellness” industry is burgeoning with health claims for many conditions, but with paltry evidence for most conditions. Our concern is further heightened as CBD products are nonregulated raising issues about molecular content and contaminants that could adversely affect patient health.
In this highly charged and often polarized environment of medical cannabis, it is more than ever critical that the medical community adhere to the standards of evidence-based medicine that were diligently developed in the last decades. The literature pertaining to cannabis is voluminous and abounds with publications of varying quality, requiring critical reading and need to question some published conclusions. Almost any hypotheses about cannabis can at this time be bolstered by some published report.
We applaud the efforts of Dr Lake and colleagues to further the evidence for the helps and harms of cannabis-based medicines. Dr. Lake challenges our conclusion that there is limited evidence for the effect of cannabinoids in pain relief based on the often-quoted publication of the National Academies of Science, Engineering, and Medicine [1]. On scrutiny, the statements of the National Academies regarding effects in chronic pain are mostly based on the conclusions of 2 meta-analyses, Whiting et al and Andreae et al, both with flaws [2, 3]. The report by Whiting et al. included 28 studies assessing effect of any cannabinoid in chronic pain, of which only 2 were assessed as a low risk of bias, and 8 were satisfactory for analysis (1 smoked tetrahydrocannabinol, 7 nabiximols) for pain reduction of 30% and more. Odds ratio was 1.41 (95% CI 0.99 to 2.00) for cannabinoids versus placebo, but with a confidence interval that includes 1; these results are not significant (p >0.05) [2]. The effect of inhaled cannabis on neuropathic pain was reported by Andreae et al [3]. This analysis included 5 studies with 178 participants, with only 1 study lasting 4 weeks, and the others lasting hours to days, precluding any assessment of long-term effects in chronic pain conditions [3]. The National Academies conclusions on “the weight of the evidence was determined during private deliberations of subgroups of the committee”, a methodology that raises questions about the quality of the conclusions [1]. Newer reviews conclude that there is low strength of evidence for cannabinoids for treatment of neuropathic pain, with only a small effect on pain overall [4, 5]. The literature abounds with favourable reports of cannabis use in chronic pain. However, many of these studies include patients with heterogenous pain conditions, are often done in the setting of a cannabis specific provider, are observational in nature and with inconsistent outcome measures; all factors that increase the risk of bias. In sum, many reports provide poor quality evidence according to current standards of evidence-based medicine.
Dr. Lake et al. selectively cite studies on the opioid sparing effects of cannabis. The evidence (based on systematic reviews) is however different. In a 2017 systematic review Nielsen et al. assessed that pre-clinical studies provide robust evidence for cannabinoid associated opioid-sparing effect, but without evidence in clinical studies [6]. Nine clinical studies included 750 participants, with none of the 3 assessed as providing high quality evidence reporting opioid sparing effect. A single case series of 3 patients, assessed as very low-quality evidence, reported reduced opioids associated with smoked cannabis [6]. Dr Lakes references the widely quoted study by Bachhuber et al. as evidence that US states that had medical cannabis laws had a slower increase in opioid overdose mortality between 1999 and 2010, but fails to reference the updated study by Shover et al. that extended Bachhuber’s study to 2017, showing that opioid overdose mortality had increased by 23%, leading the authors to caution about drawing causal conclusions from ecological correlations [7, 8]. A further comprehensive review of epidemiological and ecological studies addressing medical cannabis association with opioid use and opioid-related harms concluded that only few studies controlled for potential confounders and many had methodological weaknesses such selection bias, cross-sectional designs, and self-reported opioid-sparing effect [9].
Harms related to cannabis can mostly be gleaned from evidence for recreational users, but several points require consideration regarding medical cannabis. Firstly, patients are likely to use cannabis regularly. Cannabis is addictive with rates of addiction reported to be over 30% for daily recreational users [10]. Therefore, it can be anticipated that addiction rates related to medical cannabis will emerge, especially in younger patients using medical cannabis. Secondly, cannabis is associated with psychomotor impairment with twice the risk for a motor vehicle accident for young healthy persons in a driving simulation test [11]. Nevertheless, the general population continues to drive after recreational cannabis use with increased self-reported risk of collision [12]. Death on the roads is related to recreational cannabis use, with increased reports of motor vehicle accidents, injury and death [13-15].
The medical community must be mindful that poor quality evidence and vigorous promotion by both physicians and industry, with considerable financial gains for both, was influential in creating the current opioid crisis [16]. Today’s hype about cannabis, with poorly substantiated benefits can easily lead to a similar, but even more widespread human disaster due to ease of access to cannabis. Once again, we strongly advocate for extreme caution when councelling patients about medical cannabis use until reliable evidence for benefits and risks are available [17].
Mary-Ann Fitzcharles1,2 , Yoram Shir2, Winfried Häuser3,4
1Division of Rheumatology, McGill University Health Centre, Quebec, Canada,
2 Alan Edwards Pain Management Unit, McGill University Health Centre, Quebec, Canada,
3Department Internal Medicine I, Klinikum Saarbrücken, Saarbrücken, Germany,
4Department of Psychosomatic Medicine and Psychotherapy, Technische Universität München, München, Germany
Address corresponding author: Mary-Ann Fitzcharles, Montreal General Hospital, McGill University Health Centre, 1650 Cedar ave, Montreal, Quebec, H3G 1A4
Tel no: (514)-934-1934#44176
Fax no: (514)-934-8239
E-mail:[email protected]
1. National Academies of Sciences, Engineering, and Medicine, The health effects of cannabis and cannabinoids: the current state of evidence and recommendations for research. 2017, Washington,DC: The National Academies Press.
2. Whiting, P.F., et al., Cannabinoids for Medical Use: A Systematic Review and Meta-analysis. JAMA, 2015. 313(24): p. 2456-73.
3. Andreae, M.H., et al., Inhaled Cannabis for Chronic Neuropathic Pain: A Meta-analysis of Individual Patient Data. J Pain, 2015. 16(12): p. 1221-1232.
4. Nugent, S.M., et al., The Effects of Cannabis Among Adults With Chronic Pain and an Overview of General Harms: A Systematic Review. Ann Intern Med, 2017. 167(5): p. 319-331.
5. Stockings, E., et al., Cannabis and cannabinoids for the treatment of people with chronic non-cancer pain conditions: a systematic review and meta-analysis of controlled and observational studies. Pain, 2018.
6. Nielsen, S., et al., Opioid-Sparing Effect of Cannabinoids: A Systematic Review and Meta-Analysis. Neuropsychopharmacology, 2017. 42(9): p. 1752-1765.
7. Bachhuber, M.A., et al., Medical cannabis laws and opioid analgesic overdose mortality in the United States, 1999-2010. JAMA Intern Med, 2014. 174(10): p. 1668-73.
8. Shover, C.L., et al., Association between medical cannabis laws and opioid overdose mortality has reversed over time. Proc Natl Acad Sci U S A, 2019. 116(26): p. 12624-12626.
9. Campbell, G., W. Hall, and S. Nielsen, What does the ecological and epidemiological evidence indicate about the potential for cannabinoids to reduce opioid use and harms? A comprehensive review. Int Rev Psychiatry, 2018. 30(5): p. 91-106.
10. van der Pol, P., et al., Predicting the transition from frequent cannabis use to cannabis dependence: a three-year prospective study. Drug Alcohol Depend, 2013. 133(2): p. 352-9.
11. Ogourtsova, T., et al., Cannabis use and driving-related performance in young recreational users: a within-subject randomized clinical trial. CMAJ Open, 2018. 6(4): p. E453-E462.
12. Mann, R.E., et al., Self-reported collision risk associated with cannabis use and driving after cannabis use among Ontario adults. Traffic Inj Prev, 2010. 11(2): p. 115-22.
13. Ramaekers, J.G., Driving Under the Influence of Cannabis: An Increasing Public Health Concern. Jama, 2018. 319(14): p. 1433-1434.
14. Asbridge, M., C. Poulin, and A. Donato, Motor vehicle collision risk and driving under the influence of cannabis: evidence from adolescents in Atlantic Canada. Accid Anal Prev, 2005. 37(6): p. 1025-34.
15. Lane, T.J. and W. Hall, Traffic fatalities within US states that have legalized recreational cannabis sales and their neighbours. Addiction, 2019.
16. Nguyen, T.D., W.D. Bradford, and K.I. Simon, Pharmaceutical payments to physicians may increase prescribing for opioids. Addiction, 2019. 114(6): p. 1051-1059.
17. Hauser, W., N.B. Finnerup, and R.A. Moore, Systematic reviews with meta-analysis on cannabis-based medicines for chronic pain: a methodological and political minefield. Pain, 2018.