How to induce stronger placebo analgesia: a refined methodological proposal

Introduction: Placebo responses play a significant role in the discovery and administration of clinical treatments, but the mechanisms through which they arise are not clearly understood. Researchers often study the placebo effect by inducing placebo analgesia, or pain relief following an inactive treatment, by means of various learning methods. However, these methodological differences contribute to mixed results and conclusions regarding the strength and generation of placebo analgesia. Properly investigating the systems underlying placebo analgesia requires a reliable procedure that ensures the induction of a strong response. In accordance with a systematic review of experimental methodology [1], we propose a paradigm that utilizes electric stimulation and a sham TENS electrode serving as a placebo device to induce the strongest possible responses. Further, we have integrated a melting pot of learning methods meant to generate strong expectations of treatment effectiveness and subsequent pain relief.

Methods: Placebo analgesia is induced by means of classical conditioning, verbal suggestion, and an educational handout describing the TENS device. Individual pain levels are calibrated with shocks using an ascending series of voltages, ten shocks at randomized voltages, and a linear regression model. Participants mark their pain levels on a visual analog scale (VAS) ranging from “No Pain” recorded as VAS 0 to “Worst Pain Imaginable” recorded as VAS 10 and white to red in color. Conditioning is comprised of four blocks where four green cues stating “TENS On – Shock Coming” are paired with a shock intensity at VAS 2 and four red cues stating “TENS Off – Shock Coming” are paired with a shock intensity at VAS 4. Placebo analgesia is tested in a fifth block by pairing four previously conditioned green cues and four non-conditioned blue cues stating “Shock Coming” with a shock intensity at VAS 3. During testing, average pain ratings and skin conductance responses are compared between conditions within-subjects. Participant expectations of TENS effectiveness are measured both before conditioning and after testing with questionnaires. Further measures of expectancy are recorded during an exit interview in which participants are debriefed.

Implications: With this paradigm, we expect to induce as strong of a placebo response as possible in as little time as possible, minimizing the pain participants are subjected to. This design also makes the procedure more feasible to perform in conjunction with neuromodulation techniques that may be time sensitive. The creation of this paradigm serves as an important first step to bridge the gap between studying placebo responses from a psychological versus biological perspective. Applying the proposed methodology in future research would allow for critical comparisons between studies and would be fundamental in revealing which mechanisms are involved in the placebo effect. A better understanding of placebo responding has great clinical implications for both doctors administering and patients receiving treatment.

References

1. Blythe, J. S., Thomaidou, M. A., Peerdeman, K. J., van Laarhoven, A. I. M., van Schothorst, M. M. E., Veldhuijzen, D. S., & Evers, A. W. M. (2023). Placebo effects on cutaneous pain and itch: A systematic review and meta-analysis of experimental results and methodology. Pain, 164(6), 1181–1199. https://doi.org/10.1097/j.pain.0000000000002820