To Mitigate Placebo Response, Test, Train and Control Expectations

The placebo effect. It’s the curse of clinical trials across indications, but it’s a particularly thorny issue for pain researchers.

In fact, along with the inability of many patients to accurately report symptoms, it may be the main challenge facing analgesic trials. Left unaddressed, these issues have contributed to the failure of many clinical trials.

Everyone understands that, especially in pain trials, outcomes are based largely on patients’ subjective reports. What’s not widely understood is that some patients are better than others at accurately reporting their pain. We have demonstrated that 20% to 30% of subjects enrolled in analgesic trials are unable to report their pain accurately.

One tool to distinguish those who can from those who can’t is the Focused Analgesia Selection Test. It uses thermal heat stimuli to identify poor pain reporters.

Research published just this year in Pain supports such an approach. It concluded that

“patients whose attention is externally directed do not perceive or report bodily sensations accurately, are more vulnerable to external cues (such as placebos), and should either be excluded from clinical trials or trained to accurately report what is being measured in the study.”¹

Screening out such patients does make sense; after all, there’s no reason to expose them to risks if they can’t provide useful information. But that’s not the only solution. Many patients can be trained. The ability to accurately report pain is a skill. Not everyone is at the same level, but patients can improve their skill with training and practice.

Equally important is staff training.

Controlling expectations

We all know the expectation of pain relief is a major driver of the placebo response in clinical trials. Addressing this starts before the first patient is enrolled.

In particular, staff training around placebo response and pain reporting has become an important part of pre-trial activities. We now know that well-trained research staff not only can avoid passing their biases down to the patients but can help patients neutralize their own expectations. For instance, the ways in which staff communicate verbally and non-verbally with patients can create or control expectations. Even a reassuring smile and pat on the back can create expectations–high expectations of personal benefit–that should be avoided. We don’t expect the site teams to be unkind, but we do train them to remain neutral.

More accurate patients

Patient training is even more important. Accurate-pain-reporting training can help patients better assess their own pain.

A 2016 randomized controlled trial of an accurate-pain-reporting training program, in patients with painful diabetic neuropathy, showed that those who receive accurate-pain-reporting training have lower variability in pain scores, a reduced placebo response, and therefore improved discrimination between active drug and placebo compared to those who do not undergo training.²

We provide psycho-educational training on accurate pain reporting and placebo response reduction and familiarize patients with the pain scales that will be used during the trial. In our work, we’ve discovered that a surprising number of clinical trial patients haven’t been taught how to use a pain scale correctly.

But it’s more than that: By getting patients to be more introspective about what’s going on inside their own bodies and training them to report their pain more accurately, we inoculate them against the external cues that drive the placebo response.

Time for a change

Training patients to be able to report their symptoms more accurately is an essential part of the clinical trial process, but it’s still happening too rarely. That’s a likely cause of failed trials not only in pain but in other indications. It’s not necessarily a failure of the treatment, but a consequence of measurement error caused by variability in the primary endpoint and inflation of the placebo response.

We now have the tools to select the right patients and train the others. By doing so, we shatter the dangerous myth that we can ignore the role of the individual in generating accurate research results. Instead, we can do better by supporting them in reporting their symptoms accurately.

This has implications for other CNS trials which also grapple with the placebo effect. As researchers note in a 2018 PLoS One paper:

“The use of training approaches in future analgesic and potentially other neurological and psychiatric clinical trials has the potential to improve assay sensitivity, reduce sample size requirements, increase the likelihood of trial success, and accelerate the development of new treatment options for those who suffer.³

As we come to shine a light on how to do better pain research, we can work with colleagues in adjacent fields to carry those principles into other therapeutics that can benefit from similar approaches. We’re looking forward to those collaborations in the coming years and perhaps usher in a new area of clinical research.

References

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1. Treister R, Honigman L, Lawal OD, Lanier RK, Katz NP. “A deeper look at pain variability and its relationship with the placebo response: results from a randomized, double-blind, placebo-controlled clinical trial of naproxen in osteoarthritis of the knee” [published online February 25, 2019]. Pain. doi:10.1097/j.pain.0000000000001538
2. Treister R, et al., Training Subjects to report their pain more accurately improves study power: Results of a randomized placebo-controlled study of pregabalin vs placebo in PDN. IASP, Japan, 2016
3. Treister R, et al. “Accurate pain reporting training diminishes the placebo response: Results from a randomised, double-blind, crossover trial.” PLoS One. 2018;13(5):e0197844. Published 2018 May 24. doi:10.1371/journal.pone.0197844