Spontaneous improvement in randomised clinical trials: meta-analysis of three-armed trials comparing no treatment, placebo and active intervention

Background: It can be challenging for patients and clinicians to properly interpret a change in the clinical condition after a treatment has been given. It is not known to which extent spontaneous improvement, effect of placebo and effect of active interventions contribute to the observed change from baseline, and we aimed at quantifying these contributions. Methods: Systematic review and meta-analysis, based on a Cochrane review of the effect of placebo interventions for all clinical conditions. We selected all trials that had randomised the patients to three arms: no treatment, placebo and active intervention, and that had used an outcome that was measured on a continuous scale or on a ranking scale. Clinical conditions that had been studied in less than three trials were excluded. Results: We analysed 37 trials (2900 patients) that covered 8 clinical conditions. The active interventions were psychological in 17 trials, physical in 15 trials, and pharmacological in 5 trials. Overall, across all conditions and interventions, there was a statistically significant change from baseline in all three arms. The standardized mean difference (SMD) for change from baseline was 0.24 (95% confidence interval -0.36 to -0.12) for no treatment, -0.44 (-0.61 to -0.28) for placebo, and -1.01 (-1.16 to -0.86) for active treatment. Thus, on average, the relative contributions of spontaneous improvement and of placebo to that of the active interventions were 24% and 20%, respectively, but with some uncertainty, as indicated by the confidence intervals for the three SMDs. The conditions that had the most pronounced spontaneous improvement were nausea (45%), smoking (40%), depression (35%), phobia (34%) and acute pain (25%). Conclusion: Spontaneous improvement and effect of placebo contributed importantly to the observed treatment effect in actively treated patients, but the relative importance of these factors differed according to clinical condition and intervention.