Trial reportPloS one2014
Randomised controlled trials may underestimate drug effects: balanced placebo trial design.
Trial report in PloS one, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers, 5 of them syntheses that pooled it.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
27 citing papers in PubMed, 5 syntheses or guidelines pooled it.
- Pooled it
- How do they add up? The interaction between the placebo and treatment effect: A systematic review.British journal of clinical pharmacology · 2022Pooled it
- Control interventions in randomised trials among people with mental health disorders.The Cochrane database of systematic reviews · 2022Pooled it
- Pooled it
- Pharmacotherapy for neuropathic pain in adults: a systematic review and meta-analysis.The Lancet. Neurology · 2015Pooled it
- Placebo response varies between different types of sham acupuncture: A randomized double-blind trial in neck pain patients.European journal of pain (London, England) · 2022Trial
- Evaluating cannabidiol (CBD) expectancy effects on acute stress and anxiety in healthy adults: a randomized crossover study.Psychopharmacology · 2021Trial
- Bimodal Release Ondansetron for Acute Gastroenteritis Among Adolescents and Adults: A Randomized Clinical Trial.JAMA network open · 2019Trial
- Trial
- Does the placebo effect modulate drug bioavailability? Randomized cross-over studies of three drugs.Journal of negative results in biomedicine · 2017Trial
- Employing open/hidden administration in psychotherapy research: A randomized-controlled trial of expressive writing.PloS one · 2017Trial
- Drug*placebo interaction effect may bias clinical trials interpretation: hybrid balanced placebo and randomized placebo-controlled design.BMC medical research methodology · 2016Trial
- Placebo-response inflation in supportive oncology symptom trials: mechanisms, methodological challenges, and design implications.Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer · 2026Review
- A novel provocation protocol to identify nocebo effects in clinical practice-a proof-of-concept n-of-1 study.Frontiers in pharmacology · 2026Article
- Decoding the impact of the placebo response in clinical trials for chronic cough.ERJ open research · 2024Article
- A systematic review and meta-analysis of randomized controlled head-to-head trials of recommended drugs for neuropathic pain.Pain reports · 2024Review
- The Placebo Effect in Psychosis: Why It Matters and How to Measure It.Biological psychiatry global open science · 2023Review
- Article
- Pain, placebo, and test of treatment efficacy: a narrative review.British journal of anaesthesia · 2019Review
- Systems pharmacogenomics - gene, disease, drug and placebo interactions: a case study in COMT.Pharmacogenomics · 2019Article
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
5 authors.
Funding
No grant is acknowledged in the PubMed record.
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, mm(2)) of pain intensity during injections.
resultsThere was a significant difference between the sum of the drug effect and the placebo effect (mean AUC 6279 mm(2) (95% CI, 4936-7622)) and the total treatment effect (mean AUC 5455 mm(2) (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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.