Expectation requires treatment to boost pain relief. An fMRI study.

This study is interesting, as it challenges the conventional “additivity” assumption in randomized controlled trials (RCTs), where true drug effects are considered to be those effects that survive after subtracting the expectation-induced nonspecific effects of the placebo arm. The authors find that the active treatment effects and the expectation-induced effects are synergistic; i.e., in the presence of active treatment, expectation induces further reductions in pain, while in the absence of active treatment, expectation fails to induce pain reduction. What is also interesting is that during the placebo session, in the absence of active treatment the subjects are unable to maintain the initial level of expectation of pain relief levels throughout the 12 pain trials, while during active treatment the level of expectation of pain relief is maintained (Fig. 2B). This highlights the reinforcing effect of true pain relief on maintaining levels of expectancy akin to “conditioning,” which in turn augments the analgesic effect of the active treatment.

These results indicate that the active treatment effects are boosted by the certainty of receiving active treatment. However, what is clearly different from an RCT is that, in an RCT, the participants in the active treatment arm never have the certainty of receiving active treatment. So in a real RCT, such a synergistic effect of expectancy on active treatment is perhaps likely to be much less.