Updates & Features
Placebo Effect and Pain – Part 3
Can patient training help address symptom reporting challenges in analgesic clinical trials?
PainSolve Editorial Team
Why may analgesic drugs fail to show efficacy in clinical trials?
Across all therapy areas, a global analysis for the period 2013–2015 shows that failure to demonstrate efficacy in phase 2 or phase 3 studies was the leading reason for discontinuing development of drugs (both investigational agents, and marketed drugs under evaluation for new indications).1 For neurologic and psychiatric disease, late-stage clinical trial failure rates are disproportionately high when compared with those for other disease areas.2
A key challenge in studies for indications such as mood disorders, Alzheimer’s disease, and pain, is that subjective outcome measures, which are known to be vulnerable to bias3 and variance,4 may be endpoints for efficacy. The placebo response is also relevant, particularly in trials of novel analgesics, where patient responses to placebo can reduce the differences observed between outcomes for the active versus control arms.5
How can inaccurate self-reporting of pain in trials be addressed?
Patient training to improve the accuracy of their pain reporting has recently been applied in an analgesic clinical trial setting in the USA, where it has shown promise for increasing the likelihood of success in such trials.6 This Grünenthal-supported pilot study (NCT02842554) was a 2-stage randomised, double-blind trial in 51 adults who had peripheral diabetic neuropathy for at least 6 months (Figure 1). In Stage-1 (Training), subjects were randomised to accurate-pain-reporting-training (APRT) or control (No-Training). The APRT participants received feedback on the accuracy of their pain reports in response to mechanical stimuli applied multiple times at different intensities, with the correlation between stimuli intensities and pain intensity reports measured using Pearson’s R2 score.
In Stage-2 (Evaluation), all participants entered a placebo-controlled, crossover trial. They received treatment with pregabalin or placebo for 10–13 days, before crossover to the alternative treatment for a similar period (a washout interval of at least 6 days separated the 2 treatment periods). Primary (24-hour average pain intensity [0–10 scale]) and secondary (current, 24-hour worst, and 24-hour walking pain intensity) outcome measures were reported at the beginning and end of each treatment period.6
APRT study findings and future perspectives
In Stage-1 of the study, the APRT patients (n=28) demonstrated significant (p=0.036) increases in R2 scores indicating improvements in pain reporting accuracy due to training. This effect was demonstrated for 70.8% of these subjects. In the second study stage, the APRT group demonstrated significantly (p=0.018) lower placebo response for the primary outcome measure versus the No-Training group (0.29 ± 1.21 vs. 1.48 ± 2.21 respectively, mean difference ± SD=-1.19 ± 1.73). No relationships were found between the R2 scores and changes in pain intensity in the treatment arm.6
This pilot study shows that pain reporting accuracy is a trainable skill that can be improved, and that this improvement in turn reduces the placebo response. The findings support further research in a larger study to confirm these observations, and have implications for future analgesic, and potentially other neurological and psychiatric clinical trials. Potential benefits of training trial participants to improve their symptom reporting include improved assay sensitivity, reduced sample size requirements, increased likelihood of trial success, and accelerated development of new treatment options for patients whose clinical needs are currently unmet.6
- Pankevich DE, et al. Neuron 2014; 84(3): 546–53
- Harrison RK. Nat Rev Drug Discov 2016; 15(12): 817–8
- Heneghan C, et al. Trials 2017; 18: 122
- Farrar JT, et al. Pain 2014; 155: 1622–31
- Tuttle AH, et al. Pain 2015; 156(12):2616–26
- Treister R, et al. PLoS ONE 2018; 13(5): e0197844. Full article online at: https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0197844