Clinical Research: Phase 1 - Phase 4

The Placebo Problem, Part 9: Training Achieves Smaller Placebo Responses

This is the ninth installment of our look at the increasingly high placebo response that is plaguing clinical trials in analgesia and psychiatry. View the other posts in the series here.

Our last post reviewed several potential strategies to reduce the placebo effect, focusing on excluding high placebo responders and alternative trial designs. Today, we’ll turn to training programs for both patients and trial staff that can decrease the placebo response and improve assay sensitivity.

Sensory training

As we discussed last week, higher baseline variability in pain ratings is associated with a greater placebo but not drug responses, and eliminating subjects with high variability is one strategy to reduce the placebo response. A second option is to train patients to become more accurate at reporting their pain so that they exhibit less of a placebo response. In a poster presented at the 2016 World Congress on Pain (IASP), researchers described pilot data from a recent clinical trial evaluating their Accurate Pain Reporting (APR) protocol in 51 subjects with painful diabetic neuropathy who received either the known analgesic pregabalin or placebo.

The APR involves stimulation of a subject’s thumbnail bed at varying intensities, recording their perceived pain levels, and then providing feedback on the accuracy of their pain reporting based on stimulation intensity. In the first stage of the trial, subjects were randomized to receive APR or no APR in a parallel, unblinded fashion. Subjects showed measurable improvements in the ability to accurately and reliably report their pain across the four training sessions.

In the second evaluation phase of the trial, subjects then received pregabalin or placebo in a randomized, double-blind crossover design. Pregabalin was not superior to placebo in the overall cohort, but subjects who received the APR had larger pregabalin effect sizes, which trended toward statistical significance, than the untrained group, and this was due to a decreased placebo response rather than an increased drug response. Variability in pain reporting was also reduced in the APR group. Although this trial was quite small, the results are nevertheless intriguing and warrant further study.

Decreasing expectancy

Several studies have examined the effect of manipulating patient expectancy on the magnitude of the placebo response. One trial of Maxalt in patients with episodic migraine found that manipulating pill labels could influence the placebo response. Placebo response was greatest in pills labeled “Maxalt,” intermediate in pills labeled “placebo or Maxalt,” and lowest in pills labeled “placebo.”

Another study assessed the effects of more in-depth patient expectancy manipulation on placebo response in asthma. Four groups of patients were used: patients received either montelukast or placebo, and high or low expectation messaging. The messaging consisted of three components: a scripted message, a computer presentation, and drug capsule appearance.

The high expectation messaging was composed of an oral script and a computer program that touted the benefits of montelukast and expressed a high probability of symptom improvement, as well as blue capsules labeled with brand name of the drug. Low expectation messaging, on the other hand, included uncertainty about whether montelukast would be effective and did not describe the drug’s benefits, as well as capsules that were white and labeled with the generic name of the drug. Consistent with greater patient expectancy producing elevated placebo effects, the high expectation group showed higher placebo responses with patient-reported outcomes about asthma symptom severity and control, but not on objective measures of lung function.

Placebo response reduction (PRR) training is a related strategy that aims to modify both patient and clinician expectancy in an effort to reduce the placebo response. To date, it’s been used in at least 19 clinical trials. It focuses on neutralizing expectations of benefit in both trial staff and patients. PRR includes staff training and quizzes to assess retention of the information, as well as a workbook and quiz for subjects that emphasizes the uncertainty of benefits derived from clinical trials.

An analysis presented at the American Pain Society annual meeting this year compared placebo response in patients with chronic low back pain from a single trial that utilized PRR to 28 trials that did not employ any placebo response reduction strategies. While this type of comparison is subject to many limitations and must be taken with a grain of salt, the analysis did find that while 38 percent of subjects in the placebo groups in the non-PRR trials had a greater than 30 percent improvement in pain, while only 19 percent of subjects in the PRR training trial did.

Taken together, these results highlight the importance of future research on the placebo-reducing benefits of these sensory and psychoeducational training approaches. Next week we’ll take a closer look at some of the individual trial-related factors such as pill color and doctor-patient interactions that can be used to manipulate expectancy, many of which have already been exploited in the studies presented today.

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