Evidence for placebo effects on physical but not on biochemical outcome parameters: a review of clinical trials

Background: Recent reviews on placebo effects in clinical trials
suggest that objective changes following placebo treatments may not
exist or, at least, have been considerably overestimated. However,
the possibility that yet unidentified subsets of parameters are
responsive to placebo treatments has not been taken into account.
Therefore, the aim of the present study is to examine the effects
of placebo treatments on objectively measured outcome parameters by
specifically focusing on peripheral disease processes. Methods: An
initial dataset was collected from a MEDLINE search for
placebo-controlled, randomized clinical trials. Trials with stable
disease conditions were identified, and the effects of placebo
treatments on peripheral outcome parameters were estimated by the
changes from baseline in the placebo groups. An explorative data
analysis was conducted in order to identify parameter classes with
differential responsiveness to placebo treatments. A subgroup
meta-analysis of a second dataset was performed to test whether the
preliminary classification would also apply to placebo effects
derived from the comparison of placebo groups with untreated
control groups. Results: The explorative analysis of outcome
parameters and strength of placebo effects yielded a classification
into responsive "physical" versus non-responsive "biochemical"
parameters. In total, 50% of trials measuring physical parameters
showed significant placebo effects, compared with 6% of trials
measuring biochemical parameters. A subgroup meta-analysis
substantiated the differential response ( physical parameters: n =
14, Hedges' pooled effect size g = 0.34, 95% CI 0.22 to 0.46;
biochemical parameters: n = 15, g = 0.03, 95% CI - 0.04 to 0.10).
The subanalysis of the second dataset supported the classification
and revealed a significant improvement for physical parameters ( n
= 20, g = 0.22, 95% CI 0.07 to 0.36) and a deterioration for
biochemical parameters ( n = 6, g = - 0.17, 95% CI - 0.31 to -
0.02). Conclusion: The results suggest that placebo interventions
can improve physical disease processes of peripheral organs more
easily and effectively than biochemical processes. This
differential response offers a good starting point for theoretical
considerations on possible mediating mechanisms, and for future
investigations in this field.