A Research Agenda on the Use of Cannabis-Based Medicines for Pain Management

A Research Agenda on the Use of Cannabis-Based Medicines for Pain Management

Medical cannabis, known colloquially by some as medical marijuana, prescriptions are on the rise in many jurisdictions around the world as patient demand and clinical evidence continue to develop. Cannabis based medicines have been utilised for a large variety of health conditions, both historically and increasingly in modern medicine, however, pain management remains among the most common uses of medical cannabis, globally. 

Pain conditions, including chronic pain, continue to affect a significant proportion of the global population, with an estimated 43% of the UK population believed to experience chronic pain in their lifetime. Despite the high incidence of chronic pain, there remains limited options for treatment and pain management. The chronic use of medications such as opioids for the management of these conditions have prompted significant safety concerns due to their high risk of abuse and overdose, in addition to questions around efficacy.

However, in recent years, an increasing number of pre-clinical and clinical studies and articles have aimed to understand the potential of cannabis and its derivatives in alleviating pains or altering pain-associated behaviours.

Recently, the President of the International Association for the Study of Pain (IASP) established a task force to “systematically examine and summarise the evidence on (1) analgesic pharmacology of cannabinoids and preclinical evidence for their antinociceptive efficacy in animal models of injury-related or pathological persistent pain, (2) the clinical efficacy of cannabis, cannabinoids, and CBMs for pain, (3) harms related to long-term use of cannabinoids, as well as (4) societal issues and policy implications related to the use of cannabinoids, cannabis, and CBMs for pain management.”

1 – Preclinical pharmacology in animal models of persistent pain

Researchers identified a total of 374 studies that met the inclusion criteria for antinociceptive effects of cannabis-based medicines, cannabinoids and endocannabinoid system modulators in rodent models of pathological or injury-related persistent pain.

The researchers reported that selective and non-selective cannabinoid receptor agonists and palmitoylethanolamide were seen to demonstrate antinociceptive (pain-blocking) potential in a range of inflammatory and neuropathic pain models. Fatty acid amide hydrolase inhibitors, monoacylglycerol lipase inhibitors, and cannabidiol (CBD) also demonstrated consistent antinociceptive effects in neuropathic pain, but yielded mixed results in inflammatory pain models. 

The researchers conclude that, overall, the results of meta-analysis indicate that “evidence from laboratory experiments supports the hypothesis of cannabinoid-induced analgesia.” However, it remains uncertain how well animal models may reflect the clinical conditions they are modelling in comparison to humans. To conclude, the researchers note that the “development and validation of improved animal models with high construct and predictive validity to address more ethologically driven behaviors, as well as transparent study design and reporting”, remain important goals within preclinical pain research – including cannabinoid research. 

2 – Clinical Trials of Analgesic Efficacy

A systematic review of studies on the analgesic potential of cannabis, including in patients with acute or chronic pain receiving cannabinoid products of any type and delivered by any route. Only randomised controlled trials with 30 or more participants were included in this review. A total of 36 trials qualified for inclusion in the review, focusing mostly on cancer pain, acute pain, multiple sclerosis-related pain, and neuropathic pain, as well as musculoskeletal pain and abdominal pain.

The review authors rated these studies as having either an unclear or high risk of bias. Furthermore, all outcomes were judged as low-quality of very low-quality evidence for all types of cannabis-based medicines, regardless of the type of pain. The authors conclude that more high-quality randomised controlled trials are required to improve confidence around the potential use of medical cannabis in this capacity. 

The review also included several recommendations and research priorities that should be considered in future research in this area, such as the inclusion of pain intensity as an outcome measure and, in the context of chronic pain, “also the assessment of effects on sleep, quality of life, function, and the affective-motivational and cognitive dimensions of the pain experience, particularly those most important from the patient perspective.”

The authors also note that future RCTs should pay special attention to drug-drug interactions, particularly concerning drugs that are in widespread clinical use.

3 – Reviews of Harms Associated with Medical Cannabis Use

A total of 79 reviews which investigated the “psychiatric and psychosocial harms, cognitive or behavioural harms, motor vehicle accidents, cardiovascular, respiratory, cancer-related, pregnancy concerns, and general harms” of cannabis-based medicines were included for review. The majority (72) of these studies assessed the use of cannabis (smoked, vaporised, or ingested) as opposed to single cannabinoid preparations. Most (76) of the included reviews received a “critically low” score and reviews consistently failed to register their protocols, risks of bias assessment methods and present results on risk of bias.

The review identified a variable association between self-reported cannabis use and psychosis, motor vehicle accidents, and respiratory complications. However, it is noted that population research methods using “real-world data” are needed to track and further understand harms and benefits from the highly prevalent use of non-prescribed cannabis for pain management. The authors also suggest that it would be important to “compare these outcomes with high-quality data from patients who are treated with prescribed medicinal cannabis under expert medical supervision.”

The review authors conclude that future research in this area should place an effort on identifying the following harms associated with long-term use of cannabis for chronic pain management: cognitive effects, neurodevelopmental effects, mental health conditions with emphasis on psychosis and depression, neurological effects, cannabis use disorder, pulmonary effects, effects in pregnancy and breastfeeding, effects on driving and operating machinery, cardiovascular effects, and carcinogenicity.

4 – Systematic Reviews of Cannabinoids for Pain

Fifty-four articles, with 15 distinct pain conditions were included for review. Overall, confidence in the results of these articles, using AMSTAR-2 definitions, was generally poor. Furthermore, fewer than 10% of included reviews used criteria important for assessing pain. Therefore, overall, the review authors concluded that “current reviews were lacking in quality and could not provide a basis for decision making.”

The authors recommend that future systematic reviews should “meet the Cochrane definition of systematic reviews and should provide sufficient detail to be of moderate or high confidence according to AMSTAR-2.” It is also recommended that reviews should use properly randomised, double-blind trials in patients with a defined pain condition, and should examine the potential of bias and should perform individual-level meta-analysis, where possible – among other recommendations.

5 – Societal Issues and Policy Implications of the Widespread Use of Cannabinoids for Pain

While an increasing number of countries are considering the legalisation or decriminalisation of cannabis use, the regulatory landscape has not expanded at the same rate of demand for cannabis products, placing limitations on the conduct of large-scale multi-centre clinical trials. Finally, the IASP task force was tasked to identify how local, regional, and national regulatory and legislative approaches can affect the use of medicinal cannabis for pain. 

The task force recommends that coherent policies need to be adopted by government agencies. These include the regulation of production, sales, and defining the allowable tetrahydrocannabinol (THC) contents of products that may increase safety and limit undesirable outcomes; education programs to help mitigate associated risks coupled with advertising restrictions; and specific, evidence-based legislations for motor vehicle drivers, machine operators, and aviation pilots.