The most common indication for medical cannabis, otherwise known by some as medical marijuana, as detailed by the UK Medical Cannabis Registry is chronic pain. Around half of medical cannabis prescriptions in the United Kingdom are thought to be for chronic pain. These findings are similarly seen across the world.
Chronic pain can be used to refer to a number of conditions for which pain is a major symptom – such as cancer and fibromyalgia. The causes and mechanisms of chronic pain can be difficult to understand, with the causes sometimes difficult to determine through traditional testing mechanisms such as blood tests and x-rays. Chronic pain is believed to affect approximately 20% of the global population. As the average age of the population continues to age, this is likely to rise further still.
Despite being a common indication for medical cannabis, the mechanisms through which cannabinoids and other cannabis compounds may work for chronic pain are yet to be fully elucidated. A number of studies have aimed to determine the harms and benefits of medical cannabis and cannabinoid preparations for the treatment of both non-cancer and cancer-related chronic pain. A recent systematic review and meta-analysis assessed the findings of a number of these studies.
Design and Methods of the Study
The authors of this study reviewed the existing evidence on this subject, using a number of sources to identify relevant randomised clinical trials of medical cannabis or cannabinoids versus any non-cannabis control for chronic pain, with a follow-up of one month or more. A total of 32 trials – 29 of which compared medical cannabis or cannabinoid preparations with placebo – were identified for assessment and meta-analysis in this review.
Randomised controlled trials (RCTs) that enrolled at least 20 chronic pain patients (with pain lasting 3 months or more), randomised to any form of medical cannabis or cannabinoids versus placebo or any non-cannabis comparator, and had data from follow up for at least one month, were included. Studies for multiple sclerosis were only included where patients were described as presenting with chronic pain.
Details of included studies
To standardise data extraction, each eligible trial underwent duplicate data abstraction by pairs of reviewers. If a study reported outcomes at several time points, the results from the longest follow-up was used. Information including study characteristics, treatment details, patient characteristics, and patient-important outcomes (pain, physical functioning, sleep quality, emotional functioning, role functioning, social functioning, and adverse events) were extracted.
All continuous measures were converted to a common scale on a domain-by-domain basis.
Of the 32 studies included in this review, 28 enrolled patients living with chronic non-cancer pain and four enrolled patients with chronic cancer-related pain. Types of non-cancer pain reported in the studies included neuropathic pain (n=11), spasticity related pain (n=7), nociplastic pain (n=5), nociceptive pain (n=2), medication overuse headache (n=1), and mixed chronic non-cancer pain (n=2).
While placebo was the most common control, other comparators included dihydrocodeine and ibuprofen. Medical cannabis and cannabinoid preparations included topical CBD (n=2), oral cannabidivarin (CBDV) (n=1), palmitoylethanolamide (PEA) (n=5), tetrahydrocannabinol (THC) (n=9), a combination of cannabidiol (CBD) and THC (n=14).
Outcomes for medical cannabis and cannabinoid preparations
The meta-analysis demonstrated moderate certainty evidence from 27 randomised controlled trials that, compared with placebo, non-inhaled (topical, sublingual or oral) medical cannabis “probably result in a small increase in the proportion of patients experiencing pain relief at or above the minimally important difference”. Furthermore, moderate certainty evidence from 10 studies showed that non-inhaled cannabis “probably results in a higher proportion of patients experiencing ≥30% pain reduction with medical cannabis versus placebo.”
However, these results were not mirrored in randomised controlled trials which compared medical cannabis and cannabinoid preparations with active comparators. For example, two trials compared cannabis with non-steroidal anti-inflammatory drugs (NSAIDs): the results of one of these trials suggested that PEA was inferior to celecoxib for pain relief among women with nociplastic pain; another study suggested there was no significant difference in pain relief for medication overuse headache between THC and ibuprofen.
There were no subgroup differences in pain relief based on neuropathic pain versus non-neuropathic pain or chronic non-cancer pain versus chronic cancer-related pain. Meta-regression also showed a significant association between higher loss to follow-up and less pain relief.
The findings from this review also include high certainty evidence from 15 randomised controlled trials that, compared with placebo, medical cannabis taken orally results in a very small increase in the proportion of patients experiencing an improvement of physical functioning. However, one trial that compared medical cannabis with ibuprofen suggested no difference in physical functioning.
Of the 32 studies included in this review, 16 randomised controlled trials included outcomes on reported sleep quality. The results from these studies showed that, compared with placebo, medical cannabis taken orally was associated with a significant improvement in sleep quality.
Discussion and Conclusions
Some limitations to these findings are noted, including the inability to access long-term effects of medical cannabis for chronic pain. This was since none of the eligible trials included in this review followed patients for more than 5 and a half months. Furthermore, it is noted that over two-thirds of trials explicitly excluded patients with current or prior substance use disorders or other mental health conditions, with the remaining trials not reporting whether they included these patients.
This review also identified moderate to high certainty evidence of increased adverse effects associated with medical cannabis compared to placebo. Moderate certainty evidence suggests that the oral administration of medical cannabis “probably results in a small increase in the proportion of patients experiencing transient cognitive impairment, vomiting, drowsiness, impaired attention, and nausea”.
Overall, the researchers conclude that this review demonstrates moderate to high certainty evidence that, when compared to placebo, non-inhaled medical cannabis or cannabinoids results in a small to very small increase in the proportion of patients living with chronic cancer and non-cancer pain who experience a significant improvement in pain relief, physical functioning, and sleep quality.