Is the placebo powerless? Update of a systematic review with 52 new randomized trials comparing placebo with no treatment

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Abstract
Background. It is widely believed that placebo interventions induce powerful effects. We could not confirm this in a systematic review of 114 randomized trials that compared placebo-treated with untreated patients. Aim. To study whether a new sample of trials would reproduce our earlier findings, and to update the review. Methods. Systematic review of trials that were published since our last search (or not previously identified), and of all available trials. Results. Data was available in 42 out of 52 new trials (3212 patients). The results were similar to our previous findings. The updated review summarizes data from 156 trials (11 737 patients). We found no statistically significant pooled effect in 38 trials with binary outcomes, relative risk 0.95 (95% confidence interval 0.89-1.01). The effect on continuous outcomes decreased with increasing sample size, and there was considerable variation in effect also between large trials; the effect estimates should therefore be interpreted cautiously. If this bias is disregarded, the pooled standardized mean difference in 118 trials with continuous outcomes was -0.24 (-0.31 to -0.17). For trials with patient-reported outcomes the effect was -0.30 (-0.38 to -0.21), but only -0.10 (-0.20 to 0.01) for trials with observer-reported outcomes. Of 10 clinical conditions investigated in three trials or more, placebo had a statistically significant pooled effect only on pain or phobia on continuous scales. Conclusion. We found no evidence of a generally large effect of placebo interventions. A possible small effect on patient-reported continuous outcomes, especially pain, could not be clearly distinguished from bias.