Placebo Response and Media Attention in Randomized Clinical Trials Assessing Cannabis-Based Therapies for Pain

 Filip Gedin, PhD¹; Sebastian Blomé, MSc¹; Moa Pontén, PhD¹; et al

 doi:10.1001/jamanetworkopen.2022.43848

Key Points

Question  What is the size of the placebo response in cannabinoid trials for clinical pain, and is the magnitude of placebo response associated with media attention on the trials?

Findings  This meta-analysis of 20 studies of 1459 individuals found a significant pain reduction in response to placebo in cannabinoid randomized clinical trials. Media attention was proportionally high, with a strong positive bias, yet not associated with the clinical outcomes.

Meaning  These findings suggest that placebo has a significant association with pain reduction as seen in cannabinoid clinical trials, and the positive media attention may shape placebo responses in future trials.

Abstract

Importance  Persistent pain is a common and disabling health problem that is often difficult to treat. There is an increasing interest in medicinal cannabis for treatment of persistent pain; however, the limited superiority of cannabinoids over placebo in clinical trials suggests that positive expectations may contribute to the improvements.

Objective  To evaluate the size of placebo responses in randomized clinical trials in which cannabinoids were compared with placebo in the treatment of pain and to correlate these responses to objective estimates of media attention.

Data Sources  A systematic literature search was conducted within the MEDLINE and Embase databases. Studies published until September 2021 were considered.

Study Selection  Cannabinoid studies with a double-blind, placebo-controlled design with participants 18 years or older with clinical pain of any duration were included. Studies were excluded if they treated individuals with HIV/AIDS or severe skin disorders.

Data Extraction and Synthesis  The study followed the Preferred Reporting Items for Systematic Review and Meta-analyses reporting guideline. Data were extracted by independent reviewers. Quality assessment was performed using the Risk of Bias 2 tool. Attention and dissemination metrics for each trial were extracted from Altmetric and Crossref. Data were pooled and analyzed using a random-effects statistical model.

Main Outcomes and Measures  Change in pain intensity from before to after treatment, measured as bias-corrected standardized mean difference (Hedges g).

Results  Twenty studies, including 1459 individuals (mean [SD] age, 51 [7] years; age range, 33-62 years; 815 female [56%]), were included. Pain intensity was associated with a significant reduction in response to placebo, with a moderate to large effect size (mean [SE] Hedges g, 0.64 [0.13]; P < .001). Trials with low risk of bias had greater placebo responses (q₁ = 5.47; I² = 87.08; P = .02). The amount of media attention and dissemination linked to each trial was proportionally high, with a strong positive bias, but was not associated with the clinical outcomes.

Conclusions and Relevance  Placebo contributes significantly to pain reduction seen in cannabinoid clinical trials. The positive media attention and wide dissemination may uphold high expectations and shape placebo responses in future trials, which has the potential to affect the outcome of clinical trials, regulatory decisions, clinical practice, and ultimately patient access to cannabinoids for pain relief.

https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2799017