Age and Sex as Moderators of the Placebo Response - An Evaluation of Systematic Reviews and Meta-Analyses across Medicine

Abstract

Predictors of the placebo response (PR) in randomized controlled trials (RCT) have been searched for ever since RCT have become the standard for testing novel therapies and age and gender are routinely documented data in all trials irrespective of the drug tested, its indication, and the primary and secondary end points chosen. To evaluate whether age and gender have been found to be reliable predictors of the PR across medical subspecialties, we extracted 75 systematic reviews, meta-analyses, and meta-regressions performed in major medical areas (neurology, psychiatry, internal medicine) known for high PR rates. The literature database used contains approximately 2,500 papers on various aspects of the genuine PR. These ‘meta-analyses' were screened for statistical predictors of the PR across multiple RCT, including age and gender, but also other patient-based and design-based predictors of higher PR rates. Retrieved papers were sorted for areas and disease categories. Only 15 of the 75 analyses noted an effect of younger age to be associated with higher PR, and this was predominantly in psychiatric conditions but not in depression, and internal medicine but not in gastroenterology. Female gender was associated with higher PR in only 3 analyses. Among the patient-based predictors, the most frequently noted factor was lower symptom severity at baseline, and among the design-based factors, it was a randomization ratio that selected more patients to drugs than to placebo, more frequent study visits, and more recent trials that were associated with higher PR rates. While younger age may contribute to the PR in some conditions, sex does not. There is currently no evidence that the PR is different in the elderly. PR are, however, markedly influenced by the symptom severity at baseline, and by the likelihood of receiving active treatment in placebo-controlled trials.

Neuro-Bio-Behavioral Mechanisms of Placebo and Nocebo Responses: Implications for Clinical Trials and Clinical Practice

“…Among the patient characteristics frequently accused of driving the placebo response are sex (with larger placebo responses in women) and (younger) age. Although these factors were shown to be relevant in some trials (Thijs et al, 1990;Freeman and Rickels, 1999;Rheims et al, 2008;Cohen et al, 2010;Yildiz et al, 2011;Agid et al, 2013;Arakawa et al, 2015), a recent review (Weimer et al, 2015a) of 75 systematic reviews and metaanalyses including more than 1500 trials, 150,000 patients, and 40 medical indications revealed that age and sex were not significant predictors of placebo responses in RCT, despite occasional evidence from experimental research (Aslaksen et al, 2007;Weimer et al, 2013b).…”

Placebo effects and their determinants in gastrointestinal disorders

“…19 Similarly, a high number of study visits by patients with IBD 18,20 is associated with increased placebo response rates and indicates that one of the driving factors for the placebo response is the frequency of doctor-patient interactions. 21 The reason(s) why European trials or trials with European centre participation, generate higher placebo responses in patients with ulcerative colitis 22 than trials without European involvement remains uncertain.…”

“…5 In a review of the placebo response across many medical conditions, 19 no evidence was found that sex contributes to the placebo response despite occasional reports from experimental settings suggesting otherwise, 65 and only marginal evidence that age might have a role, with younger adult patients exhibiting larger placebo response rates than older adults. This larger placebo response rate was the case in one of the IBS meta-analyses, 24 but it has also been noted that children with functional gastrointestinal diseases in general might exhibit larger placebo responses in RCTs than adolescents and adults, 116 similar to findings in attention deficit hyperactivity disorder and depression.…”

Nocebo Hyperalgesia, Partial Reinforcement, and Extinction

“…In each phase, the groups were compared by calculating difference scores between pain with and without the 'TENS' device activated (difference = pain with TENS -pain without TENS; positive scores indicated nocebo hyperalgesia) that were analysed via mixed ANCOVAs with group and trial as factors, controlling for age and gender. Age and gender were included as covariates as both have been found to influence pain perception in general [21,38] as well as the placebo effect specifically [37]. However, the pattern of results were identical without these covariates included in the model.…”