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

Abstract

BackgroundIt 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.MethodsSystematic 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.ResultsWe 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%).ConclusionSpontaneous 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.

Placebo interventions, placebo effects and clinical practice

“…These reasons also explain why it is almost impossible to reliably judge in routine clinical practice whether a placebo effect has occurred. A recent analysis of trials including both a placebo and no-treatment control group also found relevant improvement in many no-treatment groups [29]. In conclusion, changes observed in patients receiving placebo over time are not a reliable way to estimate the size of placebo effects.…”

Placebo effects and their determinants in gastrointestinal disorders

“…The contribution to the placebo response in RCTs of spontaneous symptom improvement was evaluated across different clinical conditions and was shown to be ~50% and it was >50% in nausea RCTs. 13 A number of meta-analyses and systematic reviews have discussed the size of the placebo response in RCTs in gastrointestinal disorders, such as IBD, functional bowel disorders (IBS, functional dyspepsia), gastric and duodenal ulcerations and GERD. These disease-oriented meta-analyses are listed in Table 1, together with major…”

Placebo responses and placebo effects in functional bowel disorders

“…The authors concluded that spontaneous variation and recovery of the symptoms provide a major contribution to the PR (and to the drug response) noted in clinical trials. In an attempt to differentiate between spontaneous remission and 'true' PR, the authors conducted a further metaanalysis of 37 three-arm trials that included both a placebo group and a 'no-treatment' control group [33]. They showed spontaneous healing to be high in symptoms such as nausea, depression, phobia, and pain; approximately 50% of the placebo effect seen was due to spontaneous remission.…”

“…Although this seems rational in light of the reason the studies are usually conducted, to prove the clinical efficacy of a novel medication, they assume a simplified model of the PR that has recently been questioned: the additive versus nonadditive model of the PR [33]. In contrast, different methodologies are available to assess and quantify the PR itself and novel trial designs have been proposed to explore it further [34].…”