Randomised controlled trials may underestimate drug effects: balanced placebo trial design
Open accessAbstract
BACKGROUND: 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. OBJECTIVE: To 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. METHODS: We 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. RESULTS: There 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). CONCLUSION: Although 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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Heterogeneity of patient phenotypes in clinical trials may reflect various underlying mechanisms.
“Lastly, a largely debated issue concerns the heterogeneity of patient phenotypes in clinical trials, which may reflect various underlying mechanisms.55–57”
From Pharmacotherapy for neuropathic pain in adults: a systematic review and meta-analysis (2015) · cites this paper as [56]
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“47 Modification of the primary efficacy outcomes may or may not improve our ability to detect the difference be-tween active treatment and placebo.”
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“24,25,29,34 Consequently, if there exists an interaction between the placebo and drug effect, network meta-analyses become inadequate for inferring relative effectiveness and tolerability.”
Self-citationDoes the model of additive effect in placebo research still hold true? A narrative review
Boehm, K., Berger, B., Weger, U., & Heusser, P. (2017) · JRSM Open · doi:10.1177/2054270416681434 · Cited by 20 · see citing works
“The experimental studies all included healthy subjects.(26,27,42) One review specialised in neurological disorders such as Parkinson.”
BackgroundSafety and efficacy of low-dose medical cannabis oils in multiple sclerosis
Gustavsen, S., Søndergaard, H. B., Línnet, K., Thomsen, R., Rasmussen, B. S., Sørensen, P. S., Sellebjerg, F. T., & Oturai, A. B. (2020) · Multiple Sclerosis and Related Disorders · doi:10.1016/j.msard.2020.102708 · Cited by 18 · see citing works
Tondorf, T., Kaufmann, L., Degel, A., Locher, C., Birkhäuer, J., Gerger, H., Ehlert, U., & Gaab, J. (2017) · PLoS ONE · doi:10.1371/journal.pone.0187400 · Cited by 18 · see citing works
The placebo and its effects: A psychoneuroendocrinological perspective
Gaab, J. (2018) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2018.08.008 · Cited by 18 · see citing works
Kamerman, P. R., & Vollert, J. (2021) · Pain · doi:10.1097/j.pain.0000000000002468 · Cited by 17 · see citing works
Decoding the impact of the placebo response in clinical trials for chronic cough
Zhang, M., Zhang, B., & Morice, A. H. (2024) · ERJ Open Research · doi:10.1183/23120541.00335-2024 · Cited by 15 · see citing works
“…response may be less than the active response plus placebo response, especially in individuals exhibiting a high placebo response, thereby underestimating the actual efficacy of the active drug, although in more cases, individuals with a high placebo response also show a high drug response [35].”
Can insights from placebo and nocebo mechanisms studies improve the randomized controlled trial?
Vase, L. (2020) · Scandinavian Journal of Pain · doi:10.1515/sjpain-2019-0183 · Cited by 16 · see citing works
Self-citationPlacebo Analgesia From a Rubber Hand
Coleshill, M. J., George, D. N., & Mazzoni, G. A. L. (2017) · Journal of Pain · doi:10.1016/j.jpain.2017.04.004 · Cited by 16 · see citing works
Development of Synthetic Patient Populations and In Silico Clinical Trials
Zand, R., Abedi, V., Hontecillas, R., Lu, P., Noorbakhsh-Sabet, N., Verma, M., Leber, A. J., Tubau‐Juni, N., & Bassaganya-Riera, J. (2018) · Springer eBooks · doi:10.1007/978-3-319-73238-1_5 · Cited by 15 · see citing works
The Placebo Effect in Psychosis: Why It Matters and How to Measure It
Hird, E., Diederen, K. M. J., Leucht, S., Jensen, K. B., & McGuire, P. K. (2023) · Biological Psychiatry Global Open Science · doi:10.1016/j.bpsgos.2023.02.008 · Cited by 14 · see citing works
“This suggests that in contrast to an additive effect of drug and placebo components of a treatment, there can be an interaction effect wherein the treatment response is greater than the sum of its parts (26) (Figure 1).”
BackgroundRecommendations for Pharmacologic Therapy of Neuropathic Pain
Haroutounian, S., & Finnerup, N. B. (2018) · Elsevier eBooks · doi:10.1016/b978-0-323-40196-8.00050-4 · Cited by 12 · see citing works
Self-citationHammami, M. M., Hammami, S., Al-Swayeh, R., Al-Gaai, E. A., Farah, F. A., & Padua, S. J. S. D. (2016) · BMC Medical Research Methodology · doi:10.1186/s12874-016-0269-1 · Cited by 11 · see citing works
“More recently, others showed significant negative drug*placebo interaction effect of lidocaine on experimental pain [7].”
BackgroundContext Effects in Western Herbal Medicine: Fundamental to Effectiveness?
Snow, J. E. (2015) · EXPLORE · doi:10.1016/j.explore.2015.10.004 · Cited by 10 · see citing works
Placebo, usual care and wait-list interventions for all mental health disorders
Faltinsen, E., Todorovac, A., Hróbjartsson, A., Gluud, C., Kongerslev, M. T., Simonsen, E., & Storebø, O. J. (2019) · Cochrane Database of Systematic Reviews · doi:10.1002/14651858.mr000050 · Cited by 9 · see citing works
Lay People’s Ethical Attitudes To Placebo Treatment: A Q-Methodology Study
Hammami, M. M., Hammami, S., Aboushaar, R., & Aljomah, A. S. (2019) · Patient Preference and Adherence · doi:10.2147/ppa.s216565 · Cited by 9 · see citing works
Can Insights From Placebo and Nocebo Mechanism Studies Help Improve Randomized Controlled Trials?
Vase, L. (2019) · Clinical Pharmacology & Therapeutics · doi:10.1002/cpt.1580 · Cited by 9 · see citing works
Self-citationMilgrom, L. R. (2014) · European Journal of Integrative Medicine · doi:10.1016/j.eujim.2014.06.008 · Cited by 9 · see citing works
Response Expectancy and the Response to Antidepressant Medication
Kirsch, I. (2017) · EBioMedicine · doi:10.1016/j.ebiom.2017.09.038 · Cited by 8 · see citing works
“…clinical trials (RCTs) implies an assumption that drug and placebo effects are additive, but some writers have challenged this assumption (e.g., Lund et al., 2014) If they are not additive, they say, then conventional RCTs might underestimate the specific drug component of the treatment…”
BackgroundDie Allegianz von Forschenden als versteckter Moderator in der Psychotherapieforschung
Gerger, H., & Gaab, J. (2016) · Verhaltenstherapie · doi:10.1159/000443543 · Cited by 7 · see citing works
“Ein ausschließlich additives Verständnis von Placebo- und Verum-Effekten wird vielmehr durch neuere Befunde infrage gestellt [z.B. Lund et al., 2014].”
BackgroundSkyt, I., & Vase, L. (2016) · Tidsskrift for Forskning i Sygdom og Samfund · doi:10.7146/tfss.v12i23.22895 · Cited by 7 · see citing works
“…been utilized to specify the relative contribution of the drug effect and the placebo effect to an overall treatment outcome, thereby furthering the understanding of possible interactions between placebo and drug effects (Atlas et al. 2012; Lund et al. 2014; Schenk, Sprenger, Geuter & Büchel 2014).”
MethodSelf-citationMiller, L. E., Altman, R. D., & McIntyre, L. F. (2016) · Journal of Pain Research · doi:10.2147/jpr.s110675 · Cited by 7 · see citing works
“In addition, the clinical benefit of HA versus saline injections is likely underestimated since the therapeutic efficacy of active treatments is consistently lower when considerable treatment effects are observed in the control group, 18,19 such as those observed in HA studies.”
Mestre, T., Shamy, M. C. F., Benedetti, F., & Lang, A. E. (2018) · Movement Disorders · doi:10.1002/mds.27409 · Cited by 7 · see citing works
“Consequently, it was concluded that a treatment effect could be underestimated in a classical PCT design, particularly in studies with a large placebo effect.(10) The use of deception in a balanced study design raises critical ethical concerns (see below).”
BackgroundInfluentialRégnier, S. A., & Lee, X. Y. (2023) · Journal of Medical Economics · doi:10.1080/13696998.2023.2248842 · Cited by 5 · see citing works
“If the average change from baseline from weeks 1 – 12 was not reported in the publication, the mean changes from baseline to weeks 4, 8, and 12 were calculated, and the SE of the change from baseline to week 12 was used, since SE values were comparable across all timepoints.”
BackgroundMethodTwenty years after ‘Listening to Prozac but hearing placebo’. Do we hear placebo even louder?
Oronowicz-Jaśkowiak, W., & Bąbel, P. (2019) · Health Psychology Report · doi:10.5114/hpr.2019.83383 · Cited by 5 · see citing works
Mindfulness Effects on Anxiety: Disentangling the Role of Decentering and Treatment Expectations
Bos, D. P. A., Keesman, M., Roggeveen, A., Vase, L., Evers, A. W. M., & Peerdeman, K. J. (2024) · Behavior Therapy · doi:10.1016/j.beth.2024.03.004 · Cited by 5 · see citing works
Self-citationEthical considerations with using placebo treatments and effects in clinical practice
Druart, L., Annoni, M., & Blease, C. (2025) · Handbook of clinical neurology · doi:10.1016/b978-0-443-29884-4.00008-x · Cited by 4 · see citing works
Bimodal Release Ondansetron for Acute Gastroenteritis Among Adolescents and Adults
Silverman, R. A., House, S. L., Meltzer, A. C., Hahn, B. J., Lovato, L. M., Avarello, J. T., Miller, J. B., Kalfus, I. N., Fathi, R., Raday, G., et al. (2019) · JAMA Network Open · doi:10.1001/jamanetworkopen.2019.14988 · Cited by 4 · see citing works
Does the placebo effect modulate drug bioavailability? Randomized cross-over studies of three drugs
Hammami, M. M., Yusuf, A., Shire, F. S., Hussein, R. F., & Al-Swayeh, R. (2017) · Journal of Negative Results in BioMedicine · doi:10.1186/s12952-017-0075-2 · Cited by 4 · see citing works
“Differences between drug and placebo arms in clinical trials may represent not only drug pharmacological effect but also a drug*placebo interaction effect and thus may underestimate [7, 14] or overestimate [8] pharmacological drug effect.”
BackgroundHossain, M. B., & Karim, M. E. (2022) · Pharmaceutical Statistics · doi:10.1002/pst.2258 · Cited by 3 · see citing works
“mechanisms, and strict monitoring and follow-up of trials often overestimate the treatment effect,(4) while underestimating the treatment effect is also possible in some scenarios.(5) As a result, the generalizability of the study findings to a broader range of subjects, and for chronic disease settings that require m…”
BackgroundDworkin, R. H., & McDermott, M. P. (2014) · Pain · doi:10.1016/j.pain.2014.07.015 · Cited by 3 · see citing works
The Ethics of Placebo and Nocebo in Psychotherapy
Gaab, J., Locher, C., & Trachsel, M. (2021) · Oxford University Press eBooks · doi:10.1093/oxfordhb/9780198817338.013.32 · Cited by 2 · see citing works
Effects of deep brain stimulation and verbal suggestions on pain in Parkinson’s disease
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Self-citationPlacebo effects in neuropathic pain conditions
Kothari, S. F., Emborg, C., & Vase, L. (2024) · International review of neurobiology · doi:10.1016/bs.irn.2024.10.006 · Cited by 1 · see citing works
Self-citationMinimizing placebo responses in clinical trials
Emborg, C., Kothari, S. F., Finnerup, N. B., & Vase, L. (2025) · Handbook of clinical neurology · doi:10.1016/b978-0-443-29884-4.00018-2 · Cited by 1 · see citing works
Self-citationPharmacotherapyofneuropathicpain:whichdrugs, which treatment algorithms?
Attal, N., & Bouhassira, D. (2015)
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“Inadequate blinding has been specifically highlighted as a concern in medical cannabis trials, and balanced placebo designs have been proposed as one way to separate pharmacologic and expectancy-related effects in selected contexts [25, 26].”
Coenen, M., Hartmann, G., & Büttner, T. (2026) · Frontiers in Pharmacology · doi:10.3389/fphar.2026.1913605
- Authors
- Lund, K., Vase, L., Petersen, G. L., Jensen, T. S., & Finnerup, N. B.
- Affiliations
- Aarhus University Hospital (DK)
- Aarhus University (DK)
- Corresponding author
- Lund, Karen
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2014-01-08
- Volume
- 9
- Issue
- 1
- Pages
- e84104
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC3885519
- OpenAlex
- W2071723910
- Cited by
- 72
- References
- 40
- Citations by year
- 2026: 3 · 2025: 2 · 2024: 6 · 2023: 5 · 2022: 4 · 2021: 3 · 2020: 4 · 2019: 8 · 2018: 8 · 2017: 7 · 2016: 6 · 2015: 11 · 2014: 5
- FWCI
- 5.39
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- PLoS ONE (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Pfizer
- AstraZeneca
- European Federation of Pharmaceutical Industries and Associations (FP7/20072013)
- European Commission (115007, 2007–2013, FP7 2007-2013, FP7/2007)
- Astellas Pharma
- Innovative Medicines Initiative (FP7/2007‐2013, 115007)
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Pain Management and Placebo Effect
- Physical Sciences › Mathematics › Statistics and Probability › Statistical Methods in Clinical Trials
- Health Sciences › Medicine › Physiology › Pain Mechanisms and Treatments
- Keywords
- placebo effect, additivity assumption, lidocaine, experimental pain, placebo response
- MeSH terms
- Female, Humans, Lidocaine, Male, Pain, Placebos, Saline Solution, Hypertonic, Young Adult
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