Updates & Features
Mechanisms and implications of placebo and nocebo responses in clinical trials – The 5th PainSolve Webinar
Strategies to minimise and harmonise placebo responses in clinical trials
PainSolve Editorial Team
Prof. Ulrike Bingel (University Hospital Essen, Germany) kindly hosted her 3rd and final placebo effect PainSolve webinar on the 13th June 2019, titled, ‘Mechanisms and implications of placebo and nocebo responses – focus on clinical trials’. Following on from her first two webinars on mechanisms of the placebo effect and its implications on clinical outcomes, Prof. Bingel presented data on ways that the placebo effect could be modulated during randomised control trials (RCTs).
Prof. Bingel’s Presentation
Prof. Bingel began her presentation by stating what she hoped attendees would achieve from her talk: an understanding of the relevant placebo mechanisms and how this knowledge could be used to improve the design and interpretation of clinical trials.
In placebo-controlled trials, the placebo arm controls for three different factors: fluctuations in the natural course of the disease (especially important in pain conditions), co-intervention (even if participants are screened thoroughly, they may still take other drugs during the trial) and finally, the placebo response. The placebo response is an active psychological and neurobiological response by the individual that is induced by the expectation of a treatment response (e.g. analgesia). With these three factors being controlled for in one arm, to be able to measure the ‘true’ placebo response, a no-treatment control arm could be included. Being aware of the ‘true’ placebo response is especially relevant because the placebo treatment has been shown to be clinically relevant.1
Placebo responses represent an increasing challenge in RCTs, shown in the US by an increase from 18% to 30% between 1990 and 2013 in 84 RCTs in neuropathic pain.2 Prof. Bingel goes on to say that in order to curb this increase, we should aim to minimise and harmonise placebo mechanisms to increase assay sensitivity for new compounds.3 With expectancy and patient–physician communication being the main mediator of the placebo response, modulating these can help to beneficially modify the placebo response for clinical trials.1,4
Prof. Bingel then introduced an important 2015 paper by Vase et al., which showed that the placebo response was higher in the placebo arm if opioid medication was being used in the treatment arm and if a higher number of face-to-face interactions occurred between the patient and healthcare provider.5
As with all of the webinars in this placebo effect series by Prof. Bingel, interesting discussion points were brought up by participants at the end of the presentation. One of the discussion points led to Prof. Bingel speculating whether the increase in the placebo response in clinical trials could have been influenced by the fact that drugs can be advertised in the US. This may mean that this trend may not be seen as much in European data, however, an equivalent European study has not been performed to Prof. Bingel’s knowledge.
Training of healthcare professionals in the implications of the placebo effect in RCTs does not seem to be standardised. However, some independent training does exist, such as hands-on practice and video tutorials, as well as specialists such as Prof. Bingel being asked to come in and give training talks. Prof. Bingel feels that this information is gradually getting through the RCT organisers, but would like to see a more standardised tutorial approach so that all aspects of patient–physician communication is consistent across studies.
The final discussion point was around objective and compound pain biomarkers. This discussion included mention of the recently published Tracey et al. paper where a multimodal biomarker of pain that incorporates different physiological aspects was proposed. Further information about this paper can be found here in a recent PainSolve Paper of the Month edition. Prof. Bingel alluded to the ‘neurological pain signature’, which uses brain imaging data to predict and assess an individual’s pain intensity, however to date this brain pattern has only been validated to track the intensity of experimental pain, not for clinical pain states.6 The importance of an objective pain intensity measure is important because the more subjective the pain intensity measure, the more susceptible it is to placebo responses. Another important factor discussed, is the randomisation of the study and/or the information given about the randomisation process, which is thought to modulate the placebo effect in RCTs; if an RCT participant is aware that there is a higher chance that he/she is a going to receive the placebo instead of the treatment drug, the expectation of treatment will be modulated. This, along with many other factors, impact the placebo response. Therefore, awareness of these factors by those running RCTs could help lead to minimisation of the placebo effect and an increased chance of a significant treatment response being observed.3
- Kaptchuk TJ, et al. BMJ. 2008;336:999–1003
- Tittle AH, et al. Pain 2015;156:2616–26
- Enck P, et al. Nat Rev Drug Discov. 2013;12:191–204
- Bingel U, et al. Sci Transl Med. 2011;3:70ra14
- Vase L, et al. Pain 2015;156:1795–802
- Wager T, et al. N Engl J Med 2013; 368:1388-1397