Bottom line
Reviews of preclinical research and clinical safety and efficacy of cannabis and cannabinoids for pain relief have identified important research gaps. Due to the lack of high-quality clinical evidence, the International Association for the Study of Pain (IASP) does not currently endorse general use of cannabis and cannabinoids for pain relief. International Association for the Study of Pain recognizes the pressing need for preclinical and clinical studies to fill the research gap, and for education on this topic.
Statement
The IASP works to support research, education, clinical treatment, and better patient outcomes for all pain conditions with the goal of improving pain relief worldwide. As the leading multidisciplinary association representing healthcare professionals and scientists from 134 countries, IASP is mindful of its overriding duty to protect the public from harm.
International Association for the Study of Pain is aware of the current political and public interest in the potential applications of cannabis, cannabis-based medicines, and modulators of the endocannabinoid system in the context of pain management. This position statement solely examines the scientific evidence related to pain management and does not address other therapeutic areas. Debates regarding the laws governing the “recreational” use of cannabis were not considered. The development of this position statement has been informed by a robust and transparent review of the scientific evidence, which also enabled us to enunciate a research agenda.
Preclinical research
There have been major advances over the last 3 decades in our understanding of the physiology of the mammalian endocannabinoid system and in the pharmacology and chemistry of cannabis, cannabinoids and drugs modulating the endocannabinoid system. The biological prerequisites for cannabinoid analgesia, both endogenous and exogenous, are present in mammals (Ref to WP1 narrative review), and represent promising targets for analgesic drug development. Nevertheless, cannabinoids modulate multiple and disparate physiological processes, particularly within the brain, so the potential for producing adverse effects must also be considered. Our systematic review and meta-analysis examined 171 different cannabinoids, cannabis-based medicines and endocannabinoid system modulators that were tested for antinociceptive efficacy in rodent (predominantly male) models of injury-related or pathological persistent pain. Small molecule CB1 and CB2 receptor agonists and fatty acid amide hydrolase inhibitors were the most frequently assessed. The data support the concept of cannabinoid-mediated analgesia and reveal a spectrum of antinociceptive efficacy that is, dependent on drug class, compound, and pain model type. Selective CB1, CB2 and non-selective cannabinoid receptor agonists (including Delta-9-tetrahydrocannabinol [THC]), and palmitoylethanolamide demonstrated antinociceptive efficacy in a broad range of inflammatory and neuropathic pain models. Fatty acid amide hydrolase inhibitors, monoacylglycerol lipase inhibitors and cannabidiol consistently demonstrated antinociceptive efficacy in neuropathic pain models, but yielded mixed results in inflammatory pain models. As is the case with most preclinical systematic reviews, it was difficult to ascertain precisely the impact of risk of bias on the published data from animal model studies because the relevant factors are historically not reported. This introduces an unavoidable element of uncertainty into estimates of efficacy in animal models and we make recommendations in this regard in the research agenda. A striking discrepancy is apparent between the large number and diversity of cannabinoid interventions tested in preclinical rodent studies and the limited number and diversity of agents tested in clinical trials. Substantial evidence from laboratory experiments supports the hypothesis of cannabinoid-induced analgesia. The challenges of translating preclinical findings into safe and efficacious medicines should not be underestimated.
Clinical trials
Existing evidence for clinical efficacy in various pain conditions was scrutinised using established transparent and rigorous methods for assessing clinical evidence. Fifty-seven self-declared systematic reviews were predominantly of critically low (41) or low (8) quality (AMSTAR-2). A new systematic review and meta-analysis used highest established quality standards; it included 36 randomised controlled trials involving 7217 participants. Trials examined mainly nabiximols (a cannabis-based medicine; CBM), synthetic delta-9-THC (a cannabinoid) or cannabis. All trials were judged to be of unclear or high risk of bias and the resulting evidence was low or very low-quality, for cannabis, cannabinoids, and CBM in people with any type of pain. The taskforce did not find any moderate- or high-quality evidence. Very low-quality evidence for statistical reduction of pain intensity was found for cannabis (<7 days treatment duration) and nabiximols (>7 days treatment duration), meaning little certainty can be placed on such effects.
More adverse or unwanted events occurred in people taking cannabis or CBM compared to people in the control group not taking cannabis or CBM. No included study examined cannabidiol (a cannabinoid), and no studies included children or were exclusively with older adults. The evidence neither supports nor refutes the use of cannabinoids, cannabis or CBM in the management of pain.
Potential for harm
There are concerns about the potential for harms of cannabis and cannabinoids. The relevance of these harms to the therapeutic environment needs clarification, especially in scenarios of high dose and/or long duration of use for the treatment of chronic conditions. From the randomized placebo-controlled trials of participants with clinical pain conditions, the evidence on harms of cannabis and cannabinoids is limited and points to common (>10%) non-life-threatening adverse effects such as dizziness, sedation and fatigue. High-quality harms data from long-term controlled studies for chronic non-cancer pain are lacking. Lessons learned from the significant and enduring individual and societal effects of oversupply and overuse of opioids for chronic non-cancer pain management in some parts of the world emphasize the need to consider harms evidence from a much broader range of populations and settings of substance administration, rather than considering only results from controlled trials. Indirect evidence from population studies involving nonmedical use of cannabinoids suggests an association with harms including psychosis, cognitive effects in adolescents and young adults, motor vehicle accidents, respiratory problems, and low birth weight in infants of cannabis exposed mothers. Thus, as research on harms continues to improve and intensify, the use of cannabis and cannabinoids to treat pain should be based on thoughtful consideration of all available and emerging harms evidence when making risk-benefit treatment decisions.
Regulation and markets
International Association for the Study of Pain is concerned that in certain jurisdictions the marketing and use of medicinal cannabis has been introduced with insufficient regard for conventional and well-established regulatory safeguards and standards pertaining to medicines. This effectively removes a major incentive to the conduct of essential high-quality clinical trials necessary to establish efficacy and safety. The pharmaceutical industry regulatory standards for manufacturing, quality control, and marketing activities are being sidestepped. International Association for the Study of Pain is concerned that rigorous medical safeguards are often not in place for people who obtain and use cannabis for pain management purposes without appropriate clinical advice and supervision.
The considerable business and tax implications from the rapidly evolving recreational and medicinal cannabis industries are conflicts in political decision making. Adoption of strict policies on the regulation of production, sales, and allowable THC and contaminants contents of cannabis products may increase their safety. Banning of advertising and promotion, together with strong public education programs targeting vulnerable groups such as adolescents and pregnant women, can help mitigate some of the societal harms. Implementation and reinforcement of evidence-based approaches for limiting driving and operating machinery under the influence of psychoactive cannabinoids can help reduce the amount of accidents. Since the speed at which cannabinoid markets are growing outpaces the speed at which high-quality data are generated, the measures to mitigate individual and societal harms should be implemented rapidly.
Conclusion
Reviews of preclinical research and clinical safety and efficacy of cannabis and cannabinoids for pain relief have identified important research gaps. Due to the lack of high-quality clinical evidence IASP does not currently endorse general use of cannabis and cannabinoids for pain relief. International Association for the Study of Pain recognizes the pressing need for preclinical and clinical studies to fill the research gap, and for education on this topic.
Basic science advances are promising, but these are yet to be fully translated to efficacious and safe medicines. There is a need to increase our understanding of the biology of the endocannabinoid system. High-quality research is required to elucidate the types of pain, and characteristics of individuals, where there is benefit or harm from particular cannabinoid compounds (personalised medicine). Improved understanding of the clinical pharmacology of cannabis and cannabinoids in a pain relief setting is needed. Expansion in the range of chemical entities tested, elucidation of dose effects, and the optimisation of drug delivery is required.
As a global multidisciplinary organization of health and science professionals, IASP has a duty to protect public health, although IASP recognises that some jurisdictions already permit the use of cannabis and cannabinoids for pain relief, other medical indications, or recreational use. More research is required to elucidate the benefits and harms of therapeutic use of cannabis and cannabinoids for the treatment of pain.
A lay summary can be found on the IASP website at: https://www.iasp-pain.org/summarystatement
IASP Presidential Task Force on Cannabis and Cannabinoid Analgesia:
Chair: Andrew Rice, United Kingdom
Lars Arendt-Nielsen, Denmark
Joletta Belton, USA
Fiona Blyth, Australia
Louisa Degenhardt, Australia
Marta Di Forti, United Kingdom
Chris Eccleston, United Kingdom
David Finn, Ireland
Nanna Finnerup, Denmark
Emma Fisher, United Kingdom
Ian Gilron, Canada
Simon Haroutounian, USA
Andrea Hohmann, USA
Eija Kalso, Finland
Elliot Krane, United Kingdom
Andrew Moore, United Kingdom
Mike Rowbotham, USA
Nadia Soliman, United Kingdom
Mark Wallace, USA
Nantthasorn Zinboonyahgooon, Thailand
