Updates & Features
Placebo Effect and Pain - Part 2
June 2018
Future directions to minimise ‘false negatives’ in pain trials
PainSolve Editorial Team
Given that there is a measurable placebo response in pain and that the impact of this effect may be increasing over time, there is considerable interest in adapting pain clinical trial methodologies and designs to reduce the likelihood of ‘false negative’ trial outcomes due to large pain reductions in the placebo group.1 Several strategies have been proposed for this (see table 1 below):
Table 1: Potential approaches to take account of the placebo response in pain trials
| Approach | Potential benefit |
| Using a placebo lead-in phase (where all participants are on placebo) | Allowing investigators to engage the placebo response prior to randomisation to active drug and placebo control conditions, and to then identify and remove participants who exhibit strong placebo response2 |
| Informing patients in trials about placebo effects | Providing information leaflets about the potential for disease-specific symptom improvement when taking a placebo, thus reducing therapeutic misconceptions among participants3 |
| Assessing patients’ expectations for treatment | Using a scale for the measurement of patients’ expectations about the therapy they are receiving, and then using the results of this assessment as a co-variable when interpreting trial endpoints4 |
| Using functional imaging as an objective assessment of pharmacological responders | When applied to early proof of concept studies this approach can reduce the reliance on subjective measures of pain response by distinguishing between neural activity arising from pharmacological analgesia versus placebo response6 |
| Analysis of published trial data to identify potential factors influencing the magnitude of placebo response | This approach has been applied in neuropathic pain5 and fibromyalgia7, and has identified patient demographic and baseline characteristics associated with elevated placebo response in these conditions |
| Identifying genetic signatures associated with variations in placebo responses | Although this approach is at an early stage, research is underway to identify the ‘placebome’: a group of genome-related mediators that affect an individual's response to placebo treatment, thus allowing researchers to minimise the effect of the placebo response in clinical trials8 |
For researchers, excluding trial participants who are identified as being high placebo-responders may reduce the generalisability of the trial’s findings to real-world practice (where they would not be excluded from treatment) and increase the number of patients who need to be enrolled in a study.1 Thus, ensuring that variations in placebo response level between patients are identified and assessed as a co-variable (similar to other variables such as age, sex, BMI) may be a preferable approach. Management options for chronic pain are still suboptimal for many conditions, so understanding and addressing the challenge of the placebo response in clinical trials will be essential when developing more effective treatment options for patients and their healthcare providers.
References
- Gilron I. Expert Rev Clin Pharmacol 2016; 9: 1399–1402
- Harden RN, et al. Pain Medicine 2016; 17: 2305–2310
- Blease CR, et al. BMJ 2017; 356: j463
- Frisaldi e, et al. Pain Ther 2017; 6: 107–110
- Arakawa A, et al. Clin Drug Investig 2015; 35: 67–81
- Wanigasekera V, et al. Br J Anaesth 2018; 120: 299–307
- Chen X, et al, Clin Rheumatol 2017; 36: 1623–1630
- Scutti S. CNN 2016 Health, The real -- and growing -- effects of fake pills. Available at: https://edition.cnn.com/2016/10/27/health/placebo-effect-back-pain/index.html (accessed 18 April 2018)