title: Predictors of the placebo analgesia response in randomized controlled trials of chronic pain: a meta-analysis of the individual data from nine industrially sponsored trials.
abstract: A large number of analgesics have failed to prove superiority over placebo in randomized controlled trials (RCTs), and as this has been related to increasing placebo responses, there is currently an interest in specifying predictors of the placebo response. The literature on placebo mechanisms suggests that factors related to patients' expectations of treatment efficacy are pivotal for the placebo response. Also, general characteristics of RCTs have been suggested to influence the placebo response. Yet, only few meta-analyses have directly tested these hypotheses. Placebo data from 9 industrially sponsored, randomized, double-blind, placebo-controlled, multicenter phase III trials in 2017 adult patients suffering from chronic painful osteoarthritis (hip or knee) or low back pain were included. The primary outcome was pain intensity. Based on previous studies, we chose 3 expectancy-related primary predictors: type of active medication, randomization ratio, and number of planned face-to-face visits. In addition, explorative analyses tested whether RCT and patients' characteristics predicted the placebo response. Opioid trials, a high number of planned face-to-face visits, and randomization ratio predicted the magnitude of the placebo response, thereby supporting the expectancy hypothesis. Exploratory models with baseline pain intensity, age, washout length, and discontinuation because of adverse events accounted for approximately 10% of the variability in the placebo response. Based on these results and previous mechanisms studies, we think that patients' perception of treatment allocation and expectations toward treatment efficacy could potently predict outcomes of RCTs.
authors.affiliation: Department of Psychology and Behavioural Sciences, School of Business and Social Sciences, Aarhus University, Aarhus, Denmark Danish Pain Research Center, Aarhus University Hospital, Aarhus, Denmark Department of Pain Medicine, University Clinic Bergmannsheil, Bochum, Germany Department of Biometrics, Biogen Idec, Cambridge, MA, USA Pfizer Ltd, Global Innovative Pharma, Sandwich, United Kingdom Grünenthal GmbH, Aachen, Germany AstraZeneca Pharmaceuticals, Biostatistics and Informatics, Gaithersburg, MD, USA Division of Neuroscience, Department of Oral and Maxillofacial Surgery, University of Florida, Gainesville, FL, USA H. Lundbeck Pharma A/A, Valby, Denmark.
authors.forename: Lene
authors.initials: L
authors.lastname: Vase
authors.forename: Jan
authors.initials: J
authors.lastname: Vollert
authors.forename: Nanna B
authors.initials: NB
authors.lastname: Finnerup
authors.forename: Xiaopeng
authors.initials: X
authors.lastname: Miao
authors.forename: Gary
authors.initials: G
authors.lastname: Atkinson
authors.forename: Scott
authors.initials: S
authors.lastname: Marshall
authors.forename: Robert
authors.initials: R
authors.lastname: Nemeth
authors.forename: Bernd
authors.initials: B
authors.lastname: Lange
authors.forename: Charlie
authors.initials: C
authors.lastname: Liss
authors.forename: Donald D
authors.initials: DD
authors.lastname: Price
authors.forename: Christoph
authors.initials: C
authors.lastname: Maier
authors.forename: Troels S
authors.initials: TS
authors.lastname: Jensen
authors.forename: Märta
authors.initials: M
authors.lastname: Segerdahl
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000698:Analgesia / Q000379:methods*; D059350:Chronic Pain / Q000523:psychology* / Q000628:therapy*; D004311:Double-Blind Method; D004345:Drug Industry; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D059408:Pain Management; D010147:Pain Measurement; D015990:Placebo Effect; D011237:Predictive Value of Tests; D016032:Randomized Controlled Trials as Topic; D013223:Statistics as Topic; D016896:Treatment Outcome; D055815:Young Adult