Dr. Imran Satia’s Key Insights on Placebo Responses in Refractory Chronic Cough

Dr. Imran Satia’s Key Insights on Placebo Responses in Refractory Chronic Cough – Webinar Recap

‘Placebo Responses in Refractory Chronic Cough: Reasons and Potential Solutions’ presented by Dr. Imran Satia, explored the mechanisms, implications for clinical trials, and ethical considerations regarding placebo use in cough research. Here are just some of the key insights shared. We highly recommend watching the webinar on demand in full to experience the full breadth of Dr Satia’s insights.

1. Understanding Placebo Response vs. Placebo Effect

A key distinction discussed was between placebo response and placebo effect. Placebo response encompasses both contextual effects (e.g., patient-physician interactions, natural history, and biases) and the actual neurobiological placebo effect (involving expectancy and conditioning). The placebo effect is driven by changes in brain activity, including opioid and dopamine release, which influence cough perception.

2. Mechanisms of Placebo Response in RCC

Dr. Satia emphasised that the placebo response in RCC is a relatively new phenomenon, affecting the ability to demonstrate drug efficacy. Studies suggest that placebo effects in chronic cough might share similarities with chronic pain, involving central sensitisation and impaired inhibitory controls in the brain’s prefrontal cortex. Functional MRI studies have shown that expectancy and conditioned learning can alter cough perception and response.

3. Impact on Clinical Trials

The high placebo response in RCC trials (30-50%) complicates the evaluation of novel treatments. Early trials of gabapentin and P2X3 antagonists showed minimal placebo effects, but later-phase studies, especially for drugs like Gefapixant, demonstrated substantial placebo responses. Notably, in Phase 3 trials, placebo effects increased over time, reducing the observed difference between active treatment and placebo.

4. Factors Contributing to High Placebo Response

Several factors contribute to the high placebo response in RCC trials:

• Neurobiological Mechanisms: Activation of endogenous opioids and dopamine pathways.

• Hawthorne Effect: Increased awareness and attention during trials influence patient-reported outcomes.

• Expectation Bias: Publicised trial successes may create higher patient expectations.

• Regression to the Mean: Patients with severe symptoms at baseline may improve naturally over time, skewing results.

• Regional Differences: Placebo responses vary across geographical regions, affecting trial outcomes.

5. Potential Solutions for Clinical Trial Design

To mitigate placebo responses, alternative study designs have been proposed:

• Single-Blind Placebo Run-in Period: Patients receive placebo before randomisation to assess baseline variability.

• Threshold-Based Patient Selection: Enrolling patients with stable high cough frequency across multiple time points.

• Balanced Placebo Design: Using four study arms where patients receive either placebo or active treatment while being told different expectations.

• Sequential Parallel Group Design: Identifying placebo non-responders early and re-randomising them to active treatment.

6.  Ethical Considerations

The ethical dilemma surrounding placebo use was also discussed. The FDA and the Declaration of Helsinki have differing views on placebo controls. Ethical guidelines require justifying deception, ensuring no harm, and conducting proper debriefing. The challenge lies in balancing methodological rigor with patient welfare.

Placebo responses in RCC are significant and require strategic trial design modifications. Understanding neurobiological mechanisms, optimising patient selection, and implementing novel study designs may improve drug evaluation. Ethical considerations must also be addressed to ensure transparency and patient well-being. The webinar underscored the need for continued research and methodological advancements in RCC trials.

We highly recommend watching the webinar on demand in full to experience the full breadth of Dr Satia’s insights.

References:

• KUM, E., HASSAN, W. & SATIA, I. 2025. Placebo responses in clinical trials of refractory chronic cough: mechanisms, challenges, and mitigation strategies. The Lancet Respiratory Medicine.