Main findings

There were no temporal changes in placebo response within the analysed trials, and the response remained comparable between follow-up time points. Meta-regression analysis showed that the duration of follow-up had no effect on placebo response. The magnitude of response depended primarily on the outcome type, i.e. whether the outcome was subjective or objective. For trials with subjective outcomes, the pooled effect size of placebo response was large and it persisted for the duration of the blinded follow-up; i.e. the follow-up values did not return to baseline. However, for trials with objective outcomes, the effect was small or not significant across all time points.

Strengths and limitations

This study is a comprehensive search and analysis of placebo-controlled surgical RCTs identified through a systematic search. It is, to the best of our knowledge, the first study to characterize temporal changes in response in the placebo arm of surgical RCTs.

Data could not be included from 41 out of 88 identified trials, because the primary outcomes were binary, reported as medians with IQRs or were not associated with any data that could be extracted from the text or the figures. We did not include secondary outcomes.

Within studies eligible for inclusion, analyses were limited to the use of aggregate data, as reported by trial authors, rather than individual patient data. The lack of precision of our analyses reflected the relatively low number and small size of included studies and therefore did not investigate the effect of patient-level factors such as age, sex or expectations, which have been suggested to affect the magnitude of placebo response.

This study did not assess the effect or success of blinding, as these checks are unable to distinguish between the ineffectiveness of blinding from patient “hunches” regarding perceived treatment efficacy [39]. The effect of re-treatment could also not be investigated, as most reviewed studies used a “one-off” intervention [1], with only three studies using repeated placebo procedures. The number of follow-up time points, i.e. whether the primary outcome was assessed at the first or at a subsequent visit, was not used in the meta-regression because it was correlated with follow-up time.

We have performed a meta-analysis of placebo response under the assumption that the placebo intervention is inactive, and therefore comparable across trials. Few trials evaluated similar conditions or interventions or used comparable follow-up time points; for example, the included 47 trials investigated 28 different conditions. Thus, our ability to explain the potential sources of heterogeneity through subgroup and meta-regression analysis was limited, and much of the heterogeneity remained unexplained. Some heterogeneity may have been related to factors we did not investigate. It has been demonstrated by Vase and colleagues [7] that most of the between-trial heterogeneity is caused by patient-level characteristics (to which we had no access) rather than trial-level factors.

Interpretation

It is likely that the placebo response is not just the true placebo effect, which has been demonstrated to be small [4, 38], but possibly also the result of concomitant treatment, natural history of the disease and regression to the mean, which are discussed in more detail in the following paragraphs.

We could not investigate the extent to which placebo response is caused by the true placebo effect, because only one reviewed trial included a non-interventional group [40] that could be used to control for the natural history of disease and other non-specific changes [4]. It is plausible that the sustained large placebo response in trials with subjective outcomes may be a result of the physiological effects directly related to placebo [9]. From the extensive analysis by Hróbjartsson and Gøtzsche [4, 17, 41, 42], it is thought that the magnitude of the true placebo effect is generally small in clinical trials, and that placebo response is primarily driven by non-specific bias. A recent meta-analysis of pharmacological trials showed that the effect size in the placebo arm was indeed larger than in the non-interventional control arm, which suggests that placebo manipulation exerts some additional effect beyond non-specific changes [6].

The persistence of placebo response has been explained in terms of “the learning theory”; i.e. after the withdrawal of a cue the response does not stop immediately but gradually declines [43]. However, in the analysed trials there was no significant reduction of the placebo response.

Some of the improvement in the placebo arm might be related to the effect of concomitant treatment. It is often assumed that the placebo intervention is truly inactive and that it does not affect the response in the placebo group by means other than psychological [44]. However, most of the trials in this review used concomitant treatments liable to induce physiological or pharmacological effects, i.e. standard treatments such as anti-parkinsonian drugs, rescue medications such as analgesics or lifestyle modifications, for example diet or exercise. Therefore, although this study aimed to include only purely surgical trials, the response in the placebo arm might encompass other treatments as opposed to being solely the true placebo effect and bias. This may explain a larger effect in trials on obesity at the beginning of the follow-up period with diet and exercise having short-term effects but not long-term effects.

Part of the response in the placebo arm may be associated with non-specific factors, such as regression to the mean and the natural history of the disease. For example, a meta-analysis of pain trials reported that higher pain scores at baseline correlated with a larger placebo response [7]. It is likely that the sustained positive change in the placebo arm of trials with subjective outcomes, especially pain, is to some degree an effect of “being in the trial”, i.e. receiving additional attention and support from the clinical staff; the latter being reported as the most powerful of the non-specific effects [11]. However, it is also likely that some of the observed change may be the result of patients reporting improvement out of politeness [45] or because their ratings change with improved well-being or reduced stress [46].

There have been two recent reviews of placebo effect in surgical trials with a placebo arm. Both studies concentrated primarily on the differences in response between the surgical and placebo arm, and neither of them included a comprehensive analysis of temporal changes in the magnitude of placebo response. Moreover, they differed slightly in definition of surgery and in their eligibility criteria. In one, the authors did not exclude trials investigating an invasive delivery of pharmacologically active substances, for example the intra-articular injection of steroids [9]. In the present study, such trials were not included and analyses were restricted to purely surgical studies, because of possible differences in placebo response (including information provided to the patients and patients’ expectations when a drug treatment was involved) [47]. Another recent review [10] included procedures which were excluded from this study, as they did not fulfil our definition of surgery. Trials with binary outcomes were also excluded, as this analysis was concerned only with changes in the placebo arm, unlike the study by Holtedahl et al. [9] which investigated differences between the surgical and the placebo arm. Cross-over trials and trials with only graphical representations of the outcome data were included. Therefore, only 11 out of 21 studies analysed by Holtedahl et al. [9] and 24 out of 39 trials by Jonas et al. [10] were included in this analysis.

Heterogeneity in this study was higher than in another meta-analysis of surgical RCTs (I2 = 76%) [10] but lower than in the meta-analysis of individual patient data from studies on pain in osteoarthritis (I2 = 99%) [7]. The high heterogeneity could have been caused by the lack of restrictions on the types of studies eligible for inclusion. However, there is evidence that the condition [7] and treatment procedure may have a weak effect on placebo response [9].

The effect size in the placebo arm was large for subjective outcomes, which is in line with the findings of other reviews [4, 6, 9]. The effect on pain was larger than in a meta-analysis of various therapies on musculoskeletal pain [6], but this may be related to the invasiveness of surgery relative to other treatments [6, 48].

In this analysis, there was no statistically significant effect for assessed outcomes. It is likely that assessed outcomes are less influenced by a placebo effect or bias than subjective ones, but the finding of no statistically significant effect was unexpected, especially as a significant effect for assessed outcomes has been reported elsewhere [41]. The number of included trials was small and the heterogeneity was large; therefore, there may not have been enough statistical precision to detect a genuine effect.

For trials with objective outcomes, there was no statistical evidence of significant effect in the placebo arm. This is in line with the findings of an earlier review, which reported that placebos had no significant effect on objective outcomes [4]. The lack of placebo response found by this study suggests that the bias or non-specific changes may also be small for objective outcomes.

This is the first study to investigate the temporal changes of placebo response in surgical RCTs. There have been attempts to analyse changes of placebo analgesia with time, but the observation period was in the range of minutes [46, 49], hours [43] or weeks [5]. Within these studies, three investigated single administration of a non-invasive placebo, i.e. a capsule or a jelly [43, 46, 49], and one investigated repeated application of an invasive placebo, i.e. sham acupuncture [5]. All placebo procedures resulted in significant pain relief throughout the observation period. However, only one study performed a formal analysis to investigate the effect of time, establishing it not to be significant [46].

This is the first study to use meta-regression to investigate factors affecting placebo response in surgical trials. The duration of follow-up had no effect in either univariable or multivariable analyses. The strongest predictor of placebo response was the outcome being subjective rather than objective, which is in line with other meta-analyses of true placebo effect [17]. Concomitant treatment appeared not to explain the heterogeneity present within this study. Randomization ratio had no effect on the placebo response in our analysis. Results from other trials provide conflicting evidence, with some showing that randomization ratio in favour of active treatment results in a smaller placebo response [7], whilst others show the opposite [50]. Our analysis showed that trials located in North America had a smaller placebo response than those located elsewhere. A meta-analysis of placebo response in acute migraine also reported geographic differences, with more pain-free patients in studies performed in Europe [8]. This has been interpreted as being related to differences in patients’ expectations between countries [51].

Implications

Placebo response appears to not change with time and persists for as long as patients remain blinded and participating in the trial. Therefore, it may not be possible to minimize or maximize the magnitude of placebo response by changing the timings of follow-up time points [47, 52].

This study showed that the placebo response in surgical trials with subjective outcomes is substantial. Therefore, patient-oriented outcomes such as pain, function or quality of life may not be reliable, and trials using such outcomes may not be able to estimate the true treatment effect [53]. Where the response in both arms is large and the difference between arms is small (which is the situation in some surgical RCTs [1, 10]), even a small degree of bias may diminish the perceived efficacy of the treatment [10, 54] and may require a larger sample size to demonstrate the superiority of an intervention to placebo [55]. Where possible, objective outcomes should be used to assess the efficacy of surgical trials. Where this is not possible, or where subjective outcomes are of primary interest, placebo control could be necessary to control for bias from non-specific and placebo effects. The use of non-interventional groups may also prove useful where assessors seek to disentangle non-specific and placebo effects from placebo response.

Placebo response forms part of the response in the active arm. Therefore, a larger effect in the active arm may be paralleled by a larger response in the placebo arm [56]. In clinical practice, the placebo effect may be stronger than in an RCT because the uncertainty about treatment allocation inherent to a trial might reduce the placebo effect [57, 58]. Earlier analyses reported that the placebo response explains 80% of the variance in the surgical arm [9] and 65% of the effect in the surgical arm (78% for pain and 71% for obesity) [10]. However, most of the analysed trials used concomitant treatment which might have interfered with the true placebo effect. Therefore, in these instances, the “additive model” may not be valid [47]. This model assumes that the placebo response is non-specific, and therefore, the same in the active and in the placebo arm. The implication is that, although we know that improvement in the surgical arm may not just be an effect of the critical surgical maneuver, we do not know the extent to which placebo effect and bias contribute. Furthermore, we do not have a sufficient number of placebo-controlled surgical RCTs to investigate this.