In this issue of PAIN®, Fisher and colleagues present the findings of a high-quality systematic review on cannabis, cannabinoids, and cannabis-based medicines for pain.6 This is an important and timely review that was performed as part of the IASP Task Force in Cannabis and Cannabinoid Medicines initiative.
After a broad search of the scientific literature, the authors identified 193 trials, of which 129 were excluded. Thirty-six randomized controlled trials with 7217 participants met the inclusion criteria. All were rated as having high and/or unclear risk of bias. The trials examined nabiximols, cannabis, tetrahydrocannabinol, palmitoylethanolamide, fatty acid amide hydrolase inhibitors, dronabinol, nabilone, cannabinoid receptor agonist, and tetrahydrocannabinol congener. Treatment duration was from 1 day to 15 weeks. Most studies included participants with neuropathic pain and cannabinoids that were most often adjuvant to other analgesics. A plethora of drugs and pain conditions, with some drugs not being cannabinoid receptor agonists, some being psychoactive and others not, makes interpretation difficult. The authors have taken on and completed a mammoth task.
The review concludes that there is currently no reliable evidence to support or refute the use of cannabis, cannabinoids, or cannabis-based medicine in the treatment of chronic, acute, or cancer pain. Furthermore, evidence concerning the long-term implications, ie, months or years of medicinal use of these substances, is lacking. This means that the number of patients experiencing significant pain relief from cannabinoids is very small and those patients, if they are to receive cannabinoid treatment, will need to be carefully monitored. This conclusion is disturbing because pain relief is the most commonly cited reason for the medical use of cannabinoids. Almost 50 years after the first publications describing their antinociceptive effects in animals,2,3 we still do not have strong evidence to support the use of cannabinoids in pain management. A 2018 systematic review on cannabinoids for chronic noncancer pain that used more liberal inclusion criteria concluded: “Effects suggest that number needed to treat to benefit is high, and number needed to treat to harm is low, with limited impact on other domains. It seems unlikely that cannabinoids are highly effective medicines for chronic non-cancer pain.”14 Another recent systematic review found that for adults with advanced cancer, the addition of cannabinoids to opioids did not reduce cancer pain.1 One wonders how many systematic reviews are needed before this message gets through to physicians and public health decision makers. The general public however, needs more accessible, reliable information.
Fisher et al. noted distinct underreporting of adverse effects in the included trials. This is worrying because endocannabinoids are involved in a multitude of biological processes including, but not limited to learning, memory, cognition, motor control, anxiety and depression, appetite and food intake, reward and addiction, sleep, fertility regulation, pain modulation, cardiovascular function, and immune modulation.15 The endocannabinoid system is very complex and we are far from understanding the risks of exogenously administered cannabinoids. In recent years, there has been increased focus on this, with new adverse effects emerging.9,12,13 As part of the IASP Task Force, an overview of systematic reviews summarizing the risks of harm with cannabinoids for pain treatment is currently being prepared.8
Fisher et al. asked the pharmaceutical companies to provide missing data for their review, but these requests went unheard. We too wonder why data are being withheld and we agree with the authors that this lack of openness and transparency is contrary to current good practice in science. Also, individual patient data would have assisted our understanding of individual differences in treatment response. How many of the included trials would actually fulfill the requirements that are mandatory for new drugs?
The medicalization of cannabis is on the increase. Cannabinoids are used for a variety of reasons—not just for pain, but as antiemetics, to stimulate appetite and for the relief of therapy-resistant epileptic seizures in children (cannabidiol). The evidence for efficacy and safety of cannabinoids for conditions other than pain is beyond the scope of this commentary; however, given the lack of evidence supporting their use for pain, it is legitimate to question why global medical use is increasing.
Medical cannabis is now legal in a majority of states in the United States, whereas most EU countries allow, or are considering allowing, the medical use of cannabinoids or cannabis-based products.5 The global cannabis market is rapidly growing as more countries pass legislation, with the U.S. medical cannabis market predicted to reach approximately 11 billion USD in 2020.7 Medical cannabis is synonymous with big business. A recent headline in the U.K. newspaper, The Guardian, should leave us in no doubt: “Malawi legalises cannabis amid hopes of fresh economic growth.”11 The article informs us that Malawi is just one of several south-east African states that have recently legalized medical cannabis, that the main factor driving the law change is the economic potential of the “fast-growing global medicine and industrial cannabis industry,” and that there are plans to make cannabis the “major cash crop.” Israel, Lebanon, the United States, Canada, and Denmark are examples of other countries hoping to reap economic benefits from cannabis cultivation.
Have we really not learned anything from the opioid crisis? It continued to develop, despite early systematic reviews reporting that opioids have only limited effect for chronic noncancer pain and potentially serious adverse effects.4,10 Profit was driving the sales of opioids and the same seems to be happening with cannabinoids. Strong economic forces are pushing changes in legislation and medical practice. Physicians treating pain need to be aware of these forces. The opioid crisis in the United States is a stark reminder that economic profit should not determine our therapeutic choices.
Judgement can get clouded when people are targeted by aggressive corporate marketing and deceptive advertising. How can we change minds that are already made up? Independent campaigns are needed to actively redress the misleading information. Perhaps, the cannabis industry should be made more accountable, for example, by being billed for the costs of caring for people with cannabis-related illnesses and disability?
Conflict of interest statement
The authors have no conflicts of interest to declare.
E.A. Kalso has received payment for participation in the advisory board of Orion Pharma and Pfizer.
. Boland EG, Bennett MI, Allgar V, Boland JW. Cannabinoids for adult cancer-related pain: systematic review and meta-analysis. BMJ Support Palliat Care 2020;10:14–24.
. Buxbaum DM. Analgesic activity of 9 -tetrahydrocannabinol in the rat and mouse. Psychopharmacologia 1972;25:275–80.
. Chesher GB, Dahl CJ, Everingham M, Jackson DM, Marchant-Williams H, Starmer GA. The effect of cannabinoids on intestinal motility and their antinociceptive effect in mice. Br J Pharmacol 1973;49:588–94.
. Deshpande A, Furlan A, Mailis-Gagnon A, Atlas S, Turk D. Opioids for chronic low-back pain. Cochrane Database Syst Rev 2007:CD004959.
. European Monitoring Centre for Drugs and Drug addiction: Medical use of cannabis and cannabinoids. Questions and answers for policymaking. December 2018. Available at: www.emcdda.europa.eu
. Accessed May 10, 2020.
. 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;162(S1):S45–S66.
. Frontier Financial Group Inc., Washington DC, United States. Available at: https://newfrontierdata.com
. Accessed May 3, 2020.
. Gilron I, Blyth FM, Degenhardt L, Di Forti M, Eccleston C, Haroutounian S, Moore A, Rice ASC, Wallace M. Risks of harm with cannabinoids, cannabis, and cannabis-based medicine for pain management relevant to patients receiving pain treatment: protocol for an overview of systematic reviews. PAIN Rep 2019;4:e742.
. Hindley G, Beck K, Borgan F, Ginestet CE, McCutcheon R, Kleinloog D, Ganesh S, Radhakrishnan R, D'Souza DC, Howes OD. Psychiatric symptoms caused by cannabis constituents: a systematic review and meta-analysis. Lancet Psychiatry 2020;7:344–53.
. Kalso E, Edwards JE, Moore RA, McQuay HJ. Opioids in chronic non-cancer pain: systematic review of efficacy and safety. PAIN 2004;112:372–80.
. McCool A. Malawi legalises cannabis amid hopes of fresh economic growth. The Guardian, 2020. Available at: www.theguardian.com
. Accessed May 3, 2020.
. Pacher P, Steffens S, Haskó G, Schindler TH, Kunos G. Cardiovascular effects of marijuana and synthetic cannabinoids: the good, the bad, and the ugly. Nat Rev Cardiol 2018;15:151–66.
. Patel RS, Patel J, Jaladi PR, Bhimanadham NN, Imran S, Tankersley WE. Burden of persistent vomiting with cannabis use disorder: report from 55,549 hospitalizations in the United States. Psychosomatics 2019;60:549–55.
. Stockings E, Campbell G, Hall WD, Nielsen S, Zagic D, Rahman R, Murnion B, Farrell M, Weier M, Degenhardt L. Cannabis and cannabinoids for the treatment of people with chronic noncancer pain conditions: a systematic review and meta-analysis of controlled and observational studies. PAIN 2018;159:1932–54.
. Zou S, Kumar U. Cannabinoid receptors and the endocannabinoid system: signaling and function in the central nervous system. Int J Mol Sci 2018;19:pii: E833.