Use of Placebo and Nonoperative Control Groups in Surgical Trials

Abstract

IMPORTANCENonspecific effects, particularly placebo effects, are thought to contribute significantly to the observed effect in surgical trials. OBJECTIVE To estimate the proportion of the observed effect of surgical treatment that is due to nonspecific effects (including the placebo effect). DATA SOURCES Published Cochrane reviews and updated, extended search of MEDLINE, Embase, and CENTRAL until March 2019. STUDY SELECTION Published randomized placebo-controlled surgical trials and trials comparing the effect of the same surgical interventions with nonoperative controls (ie, no treatment, usual care, or exercise program). DATA EXTRACTION AND SYNTHESIS Pairs of authors independently screened the search results,assessed full texts to identify eligible studies and the risk of bias of included studies, and extracted data. The proportion of all nonspecific effects was calculated as the change in the placebo control divided by the change in the active surgery and pooled in a random-effect meta-analysis. To estimate the magnitude of the placebo effect, we pooled the difference in outcome between placebo and nonoperative controls and used metaregression to estimate the association between the type of control group and the treatment effect (difference between the groups), adjusting for risk of bias, sample size, and type of outcome. MAIN OUTCOMES AND MEASURESBetween-and within-group effect sizes expressed as Hedges g. RESULTSIn this review, 100 trials were included comprising data from 62 trials with placebo controls (3 also included nonoperative controls), and 38 trials with nonoperative controls (32 interventions; 10 699 participants). Risk of bias across trials was comparable except for performance and detection bias, which was high in trials with nonoperative controls. The mean nonspecific effects accounted for 67% (95% CI, 61% to 73%) of the observed change after surgery; however, this varied widely between different procedures. The estimated surgical placebo effect had a standardized mean difference (SMD) of 0.13 (95% CI, −0.26 to 0.51). Trials with placebo and nonoperative controls found comparable treatment effects (SMD, −0.09 [95% CI, −0.35 to 0.18]; 15 interventions; 73 between-group effects; adjusted analysis: SMD, −0.11 [95% CI, −0.37 to 0.15]).

Participant recruitment and attrition in surgical randomised trials with placebo controls versus non-operative controls: a meta-epidemiological study and meta-analysis

“…Risk of bias was assessed according to Cochrane Risk of Bias Tool V.1.0. and detailed in a related publication by Karjalainen et al 12…”

“A wolf in sheep's clothing”: when so‐called placebo interventions are not what they seem

“…If we remain focused on placebo‐controlled trials as the gold standard, researchers may feel pressured to conduct trials that are no longer consistent with an acceptance in current practice that placebo effects are an integral part of effective therapy and/or trials that might not necessarily control for the placebo effect. There must be a clear rationale for conducting placebo‐controlled trials, and the limitations of this approach for guiding a necessary evidence base for clinical practice should be acknowledged 16‐18 . We must accept that we cannot have appropriate placebo controls for many interventions, and that calling comparison interventions “placebo controls”, when they do not necessarily control for the placebo effect, is misleading and may result in inappropriate recommendations from health professionals as well as false perceptions of treatment effectiveness by the general public.…”

Measurement of Upper Extremity–Specific Comfort and Capability

“…Using PROMs, an increasing number of surgeries are shown in simulated (placebo) surgery-controlled trials to have benefits that are largely or completely due to nonspecific effects and not related to addressing pathophysiology. 12,13 Examples where surgery that addresses pathophysiology is no better than surgery that simulates addressing pathophysiology (sham) include surgery for degenerative meniscal pathology, 14 superior labral pathology, 15 and subacromial decompression, 15 and surgery for lateral epicondylitis. 16 It is now understood that a notable proportion of capability and comfort (measured using PROMs) is related to mindset and circumstance, with a much smaller, at times unmeasurable contribution from pathology severity.…”

“…23,24,29,30,41,42 Improvements in PROM scores can occur because of nonspecific effects (unrelated to addressing pathophysiology), meaning that specific treatments such as medication, injection, referral, or surgery ought to be held to a high standard of evidence. 13 Responsiveness is addressed by measuring relative change in an instrument and relating that to a patient's sense that they have achieved a threshold of improvement. Such instruments are referred to variously as the minimal clinical difference, minimal clinically important change, minimally important difference, 43 substantial clinical benefit, and patient acceptable symptom state.…”