Do Positive Expectations Influence Placebo Response to Pain in Cannabinoid Trials?

Pain is one of the most common reasons for seeking medical care, globally, with an estimated one-third to one-half of the UK population reportedly affected by chronic or persistent pain at some point in their lifetimes. Chronic pain conditions are often associated with major disability, loss of mobility, and a significant reduction in quality of life. 

Despite the high prevalence of chronic or persistent pain, effective treatment options remain underdeveloped and ineffective. Furthermore, many common treatments for chronic pain often possess unfavourable side effect profiles and a high risk of dependence and overdose. The high prevalence of persistent pain in the general population also has significant implications as a challenge for healthcare systems and society as a whole. Therefore, developing safe and effective treatment options is an increasingly important consideration. 

Medical Cannabis and Pain

In recent years, there has been a growing interest in trying to evaluate if medical cannabis is a potential therapeutic for chronic pain. This has not only led to an increase in relevant clinical trials and other studies but also the number of patients, clinicians, and media sources interested in the potential medicinal use of cannabis-based medical products for the management of pain. Nonetheless, evidence of the analgesic effects of cannabis remains limited, with much of the existing evidence considered of low quality. 

For example, several double-blind placebo-controlled trials have demonstrated an association between cannabinoid administration and reductions in pain; however, there is also a limited superiority of cannabinoids over placebo responses. The authors of a recent systematic review hypothesise that these results indicate that “the placebo response contributes considerably to the pain reduction seen in cannabinoids in clinical trials.” 

Therefore, the researchers conducted a systematic review and meta-analysis to evaluate the size of placebo responses in double-blind, randomised clinical trials which compared cannabinoids, cannabis, and cannabis-based medicines with placebo in the treatment of clinical pain. The second aim of the study was to “examine the association of the clinical outcomes with the amount of attention and engagement each trial has received in both scientific and non-scientific contexts.”

Design and Methods of the Review

Studies that recruited participants who were at least 18 years of age and who had a clinical pain disorder of any duration were included in the review. The included studies assessed a number of cannabinoid products (synthetic and natural) which they compared with placebo controls in a double-blind setting. A total of 20 studies, including 1458 participants with pain, were included for review. 

The primary outcome of the study was the change in self-reported pain intensity from before to after treatment. The secondary outcome was the association between study effect size and Altmetric scores or Crossref citations. Altmetric scores represented the general and social media attention linked to specific included scientific articles – referred to in the review as the “nonacademic impact”. The researchers also used Crossref to quantify the number of academic citations an article received – referred to as “academic impact”. 

To evaluate the mass media effect of the articles, the researchers “extracted the headline, summary, and website address of all blogs and mass media posts connected to each of the 20 scientific articles” included in the meta-analysis. Each news item was then independently analysed to determine whether it was positive, negative, or neutral concerning the effectiveness of cannabinoids for the treatment of pain.

Findings of the Review

The included studies assessed the effects of cannabinoid preparations – including THC and/or CBD, nabilone, dronabinol, and nabiximols – on the treatment of neuropathic pain, multiple sclerosis-associated pain, and other types of chronic pain. 

Comparing active drug and placebo outcomes

The analysis found that placebo cannabinoids had a statistically significant association with pain intensity, with a moderate to large effect size. The effect size of the active drug on pain intensity was large; however, the between group-difference for active drug and placebo was not statistically significant. These findings suggest that placebo responses may “contribute significantly to the pain reduction seen in cannabinoid randomised clinical trials.” 

In line with the findings of another recent meta-analysis, the present review did not yield a significant difference between the pain-relieving effects of the active drug and placebo. However, the correlation between effect sizes in each group was high in the previous meta-analysis, indicating that the two treatment arms may share mechanisms of improvement – for example, spontaneous remission and placebo-like mechanisms of pain reduction.

Furthermore, the present analysis showed a significant association between each study’s risk of bias and the placebo effect size. It is, therefore, possible that placebo-receiving participants in trials with a low risk of bias (that successfully blinded active and placebo treatment) were more likely to maintain positive treatment expectations through the trial and thus benefit more from a placebo effect. The researchers conclude that these findings indeed suggest that placebo responses contribute significantly to pain reduction in cannabinoid clinical trials.

Expectations cumulated by media attention

The positive expectations potentially held by participants in cannabinoid clinical trials may be a direct result of media attention given to previous studies. It is seen as a potential reason why there is no clear high-quality evidence as to the effectiveness of cannabis-based medicines for chronic pain. However, the current analysis did not identify any correlation between the percentage of – nor the number of – positive news items an article received and the outcome of the cannabinoid or placebo treatment. Nonetheless, the researchers note that their results are still meaningful: articles received considerable attention in the general media, as the authors point out, “the unusually high attention and engagement linked to cannabinoid pain trials was independent of the clinical results and may uphold high expectations and placebo responses in future trials.”