Articles reporting randomised controlled trials (including long-term follow-ups and protocols) comparing an invasive procedure with a placebo procedure in living humans were included. Pilot randomised controlled trials retrieved by the review update search were included as a source of potentially useful information about methods. Interventional procedures that change the anatomy and require a skin incision or the use of endoscopic techniques were included. Placebo referred to a surgical
ReviewConsiderations and methods for placebo controls in surgical trials (ASPIRE guidelines)
Introduction
Compelling evidence of efficacy and safety, ideally based on data from randomised controlled trials (RCTs), should underpin all routine clinical therapies, and surgical therapies are no exception. Although an RCT comparing surgical treatment to no surgical treatment provides evidence of overall efficacy, this comparison does not account for specific biases, especially the placebo effect. These potential biases are particularly likely for surgical interventions, where placebo effects have been shown to have substantial magnitude and duration, often amplified by the particular context of surgical care.1, 2 A surgical placebo control can be used to minimise bias but its use can be controversial as this control poses potential risk to the patient with little potential benefit and presents ethical, design, and trial conduct challenges.
Reviews of placebo-controlled surgical trials2, 3, 4 have included their use, issues of recruitment and feasibility, and effect on outcome and serious adverse events.5, 6 These reviews have not, however, explicitly considered issues of trial design, such as the definition and content of placebo, when it is appropriate to use (or not use) a placebo control in a surgical trial, factors that should guide the choice of a placebo design, and the influence of that choice on intervention standardisation. Some information on the ethical implications of surgical placebo trials has been published.7, 8, 9, 10, 11, 12
This Review aims to provide up-to-date knowledge on all aspects of placebo controls in the evaluation of surgery. The insights are mainly based on the outputs of a workshop funded by the UK's National Institute for Health Research and Medical Research Council, which brought together an international team of interdisciplinary experts (with research experience in placebo surgery) and patients. The workshop included a systematic update of important literature, an in-depth discussion of case studies, and an explanation of direct experience and best practice. This work culminated in the production of practical guidance for researchers: the Applying Surgical Placebo in Randomised Evaluations (ASPIRE) checklist. In this Review, we have restricted our focus to studies of adults with capacity to consent to participate in surgical research.
Section snippets
Understanding the placebo context
Knowledge of the placebo effect is dominated by two main psychological theories, both of which apply to surgery. These theories are broadly labelled as conditioning, a learning theory in which placebo effects are underpinned by associative learning with the placebo paired with an active treatment to trigger a physiological response, and response expectancy, in which the placebo effects are underpinned by the patient's conscious or unconscious expectation that the placebo will have a particular
When are surgical placebo controls acceptable?
Surgical placebos might be most appropriate when there is poor evidence on the efficacy of the procedure and a justified concern that the results of an open trial would be associated with high risk of bias.
Ethical considerations are fundamental to the decision to use a surgical placebo control. Patients participating in a placebo-controlled surgical trial are at risk of a surgical intervention that does not have the presumptive causally effective element (ie, the essential surgical element).
Identifying and mitigating risk in placebo surgical trials
The ethics literature on the use of placebo surgical controls stresses the need for any potential risk from use of a placebo to be mitigated. The evidence on risk is mixed. The review by Wartolowska and colleagues3 found that surgical placebo-controlled trials did not appear to carry any greater risk than any other treatment or control group. However, most of the placebo RCTs in that review only evaluated endoscopic or minimal access interventions. A review from the Study Center of the German
Nomenclature for patients
The nomenclature for patients in surgical placebo trials is important and patient representatives are uneasy with descriptors such as deception and sham for surgical evaluation.44 Although such terms might often be seen in a scientific or trial design context, they are less acceptable to patients because of their negative connotations and should be avoided. Reporting guidelines under TIDieR (Template for Intervention Description and Replication) are being updated for placebo control (J Howick,
Interpretation and translation into change of policy and practice
In more than half of the placebo-controlled trials of surgery reported in peer reviewed literature, the results have shown no benefit of the definitive procedure compared with the placebo control.3 In many others, the placebo effect remains strong but is accompanied by a small, genuine treatment effect from the procedure. The presence of some effect from the index procedure is not surprising because of the ethical and academic justifications required for the use of a surgical placebo control.
Key messages
Our Review has described how placebo controls might justifiably be used in RCTs of surgical interventions, provided that there is a strong scientific and ethical rationale for the study. A surgical placebo control is not appropriate for all evaluations of surgery but might be best reserved for operations associated with low surgical complication risk, potentially low efficacy, unjustified usage, and in which a clinically significant placebo response is expected. In expectation of a complex set
Search strategy and selection criteria
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