Abstract
BackgroundIt is an inherent assumption in randomised controlled trials that the drug effect can be estimated by subtracting the response during placebo from the response during active drug treatment.ObjectiveTo test the assumption of additivity. The primary hypothesis was that the total treatment effect is smaller than the sum of the drug effect and the placebo effect. The secondary hypothesis was that non-additivity was most pronounced in participants with large placebo effects.MethodsWe used a within-subject randomised blinded balanced placebo design and included 48 healthy volunteers (50% males), mean (SD) age 23.4 (6.2) years. Experimental pain was induced by injections of hypertonic saline into the masseter muscle. Participants received four injections with hypertonic saline along with lidocaine or matching placebo in randomised order: A: received hypertonic saline/told hypertonic saline; B: received hypertonic saline+lidocaine/told hypertonic saline; C: received hypertonic saline+placebo/told hypertonic saline+pain killer; D: received hypertonic saline+lidocaine/told hypertonic saline+pain killer. The primary outcome measure was the area under the curve (AUC, mm2) of pain intensity during injections.ResultsThere was a significant difference between the sum of the drug effect and the placebo effect (mean AUC 6279 mm2 (95% CI, 4936–7622)) and the total treatment effect (mean AUC 5455 mm2 (95% CI, 4585–6324)) (P = 0.049). This difference was larger for participants with large versus small placebo effects (P = 0.015), and the difference correlated significantly with the size of the placebo effect (r = 0.65, P = 0.006).ConclusionAlthough this study examined placebo effects and not the whole placebo response as in randomised controlled trials, it does suggest that the additivity assumption may be incorrect, and that the estimated drug effects in randomised controlled trials may be underestimated, particularly in studies reporting large placebo responses. The implications for randomised controlled trials and systematic reviews need to be discussed.
Highlights
There was a significant difference between the sum of the drug effect and the placebo effect (mean AUC 6279 mm2) and the total treatment effect (mean AUC 5455 mm2) (P = 0.049)
Conclusion: this study examined placebo effects and not the whole placebo response as in randomised controlled trials, it does suggest that the additivity assumption may be incorrect, and that the estimated drug effects in randomised controlled trials may be underestimated, in studies reporting large placebo responses
Double-blind randomised controlled trials (RCTs), systematic reviews, and meta-analyses of RCTs are considered to be the gold standard for evidence-based treatment guidelines [1]
Summary
Double-blind randomised controlled trials (RCTs), systematic reviews, and meta-analyses of RCTs are considered to be the gold standard for evidence-based treatment guidelines [1]. Factors contributing to the response following placebo treatment may be different from those contributing to the response following drug treatment as seen in trials of depression and menopausal symptoms [12,13] Along these lines, placebos, antidepressants, and analgesics have been shown to exert different effects on the brain [14,15], so indirect evidence suggests that drug and placebo responses are only partly additive. Placebos, antidepressants, and analgesics have been shown to exert different effects on the brain [14,15], so indirect evidence suggests that drug and placebo responses are only partly additive This issue has, never been thoroughly investigated, it may have serious implications for clinical trial methodology and evidence-based medicine [5,16,17,18]. It is an inherent assumption in randomised controlled trials that the drug effect can be estimated by subtracting the response during placebo from the response during active drug treatment
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