The Placebo Response as a Confounder in Clinical Trials In Pain

Professor Nanna Brix Finnerup

Danish Pain Research Center, Department of Clinical Medicine, Aarhus University, Denmark

The recent systematic review and meta-analysis, which provided the basis for the latest recommendation on neuropathic pain pharmacotherapy,1 demonstrated large numbers needed to treat (NNT) for most neuropathic pain medications, compared with the previous guidelines. In addition, multiple recent clinical trials in neuropathic pain with preclinically promising drugs have failed. Part of the reason for decreased estimated effect sizes over time and failed trials are large placebo responses. An inherent assumption in the RCT design is that the difference between the observed analgesic drug response and the observed placebo response can be attributed to the “true” pharmacological effect of the drug. Studies using the balanced placebo design allowing an estimation of the drug effect, the placebo effect, and the combination of placebo have found that the drug treatment and placebo treatment are less than additive, i.e. the active drug effect is higher than the combined effect subtracted with the placebo effect. The predictors for high placebo responses and the implication of variable placebo responses for clinical trials, systematic reviews and evidence-based clinical treatment guidelines will be discussed.


1Finnerup NB, Attal N, Haroutounian S, McNicol E, Baron R, Dworkin RH, Gilron I, Haanpää M, Hansson P, Jensen TS, Kamerman PR, Lund K, Moore A, Raja SN, Rice AS, Rowbotham M, Sena E, Siddall P, Smith BH, Wallace M. Pharmacotherapy for neuropathic pain in adults: a systematic review and meta-analysis. Lancet Neurol. 2015;14:162-73.