Not All Placebos are Equal: The Needle is Mightier than the Pill Save

Placebos are necessary to determine the “true effect” of any medical intervention. As such, they have become the cornerstone of evidence-based medicine, randomized controlled clinical trials and novel drug development.

Factors that influence the placebo effect are many and may include the available treatment options, patient expectation, sample size, outcome measures and random events. The word placebo means “to please”, and the history of medical therapeutics prior to the 20^th century is largely the history of placebo intervention.

Placebo controls are necessary when ascertaining the benefits of a new intervention (the so-called treatment effect), but also the inherent benefits of the method of administration. It is unclear whether different placebo delivery methods yield different effects.

Bannaru and coworkers performed a network metanalysis of knee osteoarthritis trials. The purpose of these trials was to assess differential placebo effects on active-treatment effect estimates. These researchers reviewed 149 randomized trials comparing common drug interventions to four placebo delivery options: oral, intra-articular, topical, and oral plus topical. They showed intra-articular placebo (effect size of 0.29 [0.09 to 0.49]) and topical placebo (effect size of 0.20 [0.02 to 0.38]) were significantly greater than oral placebos. This finding supports the notion that placebos can exert clinically relevant effects, and that differential placebo effects need to be considered in the design of clinical trials.