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Comparing Cannabinoids with Placebo for Pain: A Systematic Review

Published: 04/03/2024

Pain is the most reported symptom among the general population. It can be associated with a wide range of conditions, co-occur with other symptoms such as insomnia and depression, and is associated with a lower degree of health-related quality of life. Pain may be categorised in various ways, such as acute pain and chronic pain or cancer and non-cancer pain.

Acute pain usually has a well-defined onset and cause (e.g., surgery, trauma) and typically resolves in 4 weeks, but can last up to 3 months before being considered as chronic pain. The onset of chronic pain may be difficult to define, and the cause is also often hard to determine; while it may also be associated with physical trauma such as surgery, it may be caused by nerve damage and dynamic changes in the nervous system.

Various treatments may be considered for the management of pain, including medical interventions such as opioids and non-steroidal anti-inflammatory drugs (NSAIDs), physical therapy and psychological therapy. In recent years, cannabinoids have emerged as a potential alternative to other painkillers which may present large risks, with limited benefit. Some research indicates that cannabinoid-based medicines may be beneficial in pain management; however, their use may also be associated with adverse events, making it crucial to weigh the benefits and harms of their use.

Chronic pain is consistently the most common reason for medical cannabis use, globally. Before healthcare systems around the world endorse the use of cannabis-based medicines for pain, however, the potential short- and long-term benefits and harms must be established.

A recent systematic review aimed to assess the benefits and harms of cannabinoids versus placebo or no intervention for participants with acute and chronic pain.

Design and Methods of the Study

The researchers conducted a systemic review with meta-analysis and Trial Sequential Analysis (TSA) of available randomised controlled trials (RCTs) to evaluate the effectiveness and safety of cannabinoids in participants with pain. Eligible RCTs were included regardless of trial design, setting, publication status, year, language, and reporting outcomes.

The primary outcomes were all-cause mortality, pain assessment using a visual analogue scale (VAS) or a numerical rating scale (NRS), the proportion of patients with one or more serious adverse events, and quality of life measured on any valid continuous scale.

Secondary outcomes included cannabinoid dependence, psychosis, proportion of patients with one or more non-serious adverse events, and quality of sleep measured on any valid continuous scale. The researchers also assessed several exploratory outcomes, including each adverse event separately, 24-hour morphine consumption, physical function, and depressive symptoms.

Results of the Study

Sixty-five randomised controlled trials including 7,017 participants were included in the review. Forty-four of these trials assessed chronic pain. Nine trials looked at medical cannabis in cancer pain, whilst 10 and 2 trials assessed acute and fibromyalgia-related pain respectively.


The length of follow-up ranged from 7 hours to 16 weeks with an average follow-up of 7.3 weeks. Only 35 trials provided data that could be incorporated into the meta-analysis. Most (59) of the trials were rated as having a high risk of bias by the authors.

Primary Outcomes

There was no difference between cannabinoids versus placebo on all-cause mortality, serious adverse events, and quality of life. Furthermore, the meta-analysis showed that cannabinoids were associated with higher reductions in chronic pain (in particular, central, and peripheral neuropathic pain) and improvement in quality of sleep; however, both effect sizes were below the minimal important differences.

Secondary Outcomes

None of the included studies reported results on the outcomes of cannabinoid dependence or psychosis that could be analysed through meta-analysis. There was also no evidence of a difference between cannabinoids versus placebo on the incidence of serious adverse events; however, cannabinoids were associated with a higher risk of non-serious adverse events. Reported non-serious adverse events included dizziness, fatigue, vertigo, nervous system disorders, and gastrointestinal disorders.

A total of 17 trials assessed quality of sleep using a numerical rating scale. Meta-analysis showed that cannabinoids were associated with larger improvements in the quality of sleep compared with placebo; however, the effect size was below the predetermined minimal important differences.

Other Outcomes

Meta-analysis of the six trials that assessed 24-hour morphine consumption and the three trials (that assessed ability to perform activities of daily living, showed no evidence of difference between cannabinoids and placebo. Five trials also showed no difference in depressive symptoms between cannabinoids and placebo.


The authors of this systematic review and meta-analysis arrive at a different conclusion to most recent reviews. This is despite the evidence seemingly producing similar outcomes. The interpretation and specific analysis of this data, however, lead to different conclusions being drawn. In this study, the authors place the emphasis on the size of effect being below the minimal important difference. In a similar study by Wang and colleagues published in the British Medical Journal, they modelled the proportion of people treated with cannabinoids who would be more likely to report a difference in symptoms. The reported increase was 10%. They reasoned that although 10% is a small proportion of individuals, the patients involved in the study indicated that a 10% improved likelihood of a clinically significant improvement in pain if they have failed previous therapies would be acceptable to them. Nonetheless, further research is required in this setting to better understand the safety and effectiveness of cannabinoid-based medicines for chronic pain more generally. In particular, there is a paucity of studies which examine the effects of vaporised dried flower.

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