Significant placebo response to pain in cannabinoid clinical trials

5th January 2023

The placebo response appears to play a significant role in pain reduction in clinical trials assessing a patient’s response to cannabinoids

A placebo response makes a significant contribution to the reduction in pain scores seen in cannabinoid clinical trials according to the findings of a systematic review and meta-analysis by Swedish researchers.

Pain is one of the most common symptoms experienced by patients in different health care settings, often leading to loss of function for the affected individual as well as a decline in their quality of life. Although there are wide range of medicines which act as pain-killers, in recent years, there has been increasing interest in the medical properties of cannabinoids. However, the evidence supporting the value of cannabinoids in pain management is limited.

In fact, a 2021 systematic review concluded on how the available evidence neither supports nor refutes claims of efficacy and safety for cannabinoids, cannabis, or cannabis-based medicines in the management of pain. These findings suggest that there may be an important placebo response in such trials and which arise from patients’ positive expectancies.

Furthermore, it is believed that different systems and mechanisms trigger placebo effects that highly impact pain processing, clinical outcomes and create a sense of well-being.

But how large is the placebo response in clinical trials examining the role of cannabinoids in the management of pain? This was the key question addressed in the current study where researchers set out to evaluate the size of placebo responses in double-blind randomised clinical trials in which cannabinoids, cannabis, and cannabis-based medicine were compared with placebo in the treatment of clinical pain. 

The researchers measured the change in pain intensity from before to after treatment, measured as bias-corrected standardised mean difference (Hedges g), which provides an assessment of the effect size. A small effect is represented by a value of 0.2, whereas a medium effect is 0.5 and a large effect 0.8.

Placebo response in cannabinoid trials

The researchers identified a total of 20 eligible trials with 1459 individuals (mean age = 51 years, 56% female). Studies included patients with neuropathic pain and multiple sclerosis.

The effect size of the active drug (cannabinoids) on pain intensity was large (mean Hedges g = 0.95, p  <0 .001). However, pain intensity was associated with a significant reduction in response to placebo, with a moderate to large effect size (mean Hedges g = 0.64, p < 0.001).

In a further analysis, the researchers looked at the media attention paid to these findings and found that this attention was independent of how biased the study was, the extent of the placebo response or how low the treatment effect was.

The authors concluded that placebos contribute significantly to the pain reduction seen in cannabinoid clinical trials. In addition, the positive media attention and wide dissemination possibly leads to high expectations and hence may shape the placebo response in future trials.

Citation
Gedin F et al. Placebo Response and Media Attention in Randomized Clinical Trials Assessing Cannabis-Based Therapies for Pain: A Systematic Review and Meta-analysis. JAMA Netw Open. 2022.

Cannabinoids likely to be of limited value in rheumatoid arthritis

28th May 2021

Cannabinoids are widely used for the management of pain but whether the treatments help the pain associated with rheumatoid arthritis is uncertain.

Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease affecting the small joints of the hands and feet. Clinically, the condition presents with swelling, heat, stiffness and pain in affected joints, warranting the use of analgesics to relieve symptoms. Cannabis and related cannabinoids are used for the management of range of painful conditions although there is uncertainty over the value of cannabis-related medicines for chronic pain. Despite this uncertainty, analysis of a US rheumatic disease registry found that nearly two-thirds of patients who used cannabis felt that it was helpful in relieving symptoms. But what is the evidence to support the use of cannabinoids in RA was the question posed by a team from the Department of Clinical Immunology and Rheumatology, Pontificia University, Chile.

Findings
A literature search identified 26 systematic reviews but within these reviews, there was only one randomised, controlled trial that specifically addressed the role of cannabinoids in RA. The study included 58 patients (79.3% female) with active RA that was inadequately controlled with standard medication including disease modifying anti-rheumatic drugs (DMARDS) and which had been used at the same dose for 3 months prior to enrolment. The trial involved the use of an oromucosal spray (nabiximols) containing 2.7mg tetrahydrocannabinol (THC) and 2.5mg of cannabidiol (CBD) and compared this with a placebo spray. A single dose was administered once daily and up-titrated every two days to a maximum of 6 doses per day for a period of 21 days. Outcomes reported included various pain measures, e.g., morning pain, pain at rest, present pain and a disease activity score.

The overall reported pain score was 3.3 vs 2.6 (nabiximols vs placebo) and disease activity score was 5.9 vs 5.0 (nabiximols vs placebo). However, there was a higher incidence of serious adverse events (74 vs 13, nabiximols vs placebo).

Commenting on the results of this single study, the authors noted that it was not possible to extrapolate the findings to other cannabis containing products or different routes of administration. The authors conclude that cannabis-related compounds may slightly reduce disease activity but that there appeared to be little, if any, effect on pain scores. Nevertheless, they did identify three ongoing, randomised clinical trials and indicated that these should provide more relevant information on the potential value of cannabinoids once published.

Citation
Schulze-Schiappacasse C et al. Are cannabis, cannabis-derived products and synthetic cannabinoids a therapeutic tool for rheumatoid arthritis? A friendly summary of the body of evidence. J Clin Rheumatol 2021