Main findings

To the best of our knowledge, this is the first meta-analysis modelling longitudinal changes in the magnitude of effect in the placebo arm of surgical RCTs across all follow-up visits. This study supports our earlier findings that, across all analyzed trials, the magnitude of placebo response does not significantly change with time; it also shows that placebo response does not change with the number of visits. However, when trials were subdivided by outcome type, for trials with subjective outcomes, the response in the placebo arm remained large and relatively constant for at least 12 months or seven visits, while for trials with objective outcomes, the improvement in the placebo arm diminished with time but not with follow-up visits. It should be noted that, unlike pharmaceutical trials, in which there may be multiple applications of a placebo regimen, all but three trials analyzed in this study used a “one-off” placebo intervention (Additional file 1).

Strengths and limitations

The main strength of this paper is that, unlike our previous analysis, we investigated the effect of time and visit number across all follow-up visits. The main limitation of this study is the paucity of data; both in the form of the number of eligible studies, and the number of observations per study.

We were not able to investigate the extent to which placebo response was caused by the so called “true placebo effect”, i.e., the difference in effect between the placebo and non-interventional arms [16], because only one trial included a non-intervention group [17]. Analyses were limited to the assessment of “placebo response”, i.e., the total change in the placebo arm between the baseline and follow-up visits. As a consequence of this, the magnitude of response may be affected by factors that are not related to placebo intervention itself, such as regression to the mean, fluctuations in disease severity, spontaneous improvement or report bias.

Seventy-nine percent of the trials used or allowed the use of standard or rescue medication [3]; therefore, some of the effect observed in the placebo group may be the result of concomitant pharmacological treatment or lifestyle modifications. We did not include any information about concomitant medication in our analysis because of the limited reporting of this characteristic in the analyzed trials.

Analyses were based on summary data, as reported by the authors of each trial. This limited the power of our analyses and did not allow us to investigate the effect of patient-related factors; therefore, we were unable to draw inference about individual patient responses (significant relationships at the population level may not hold true at the individual level and vice versa, i.e., the ecological fallacy).

The statistical modelling carried out in this study relied on several choices and assumptions. We chose to use SMDs for the outcome measure, as the reported outcome types and measures were heterogeneous, rendering standardization necessary to combine results. In a study with baseline and multiple follow-up outcome assessments, we would typically adjust for the magnitude of the outcome at baseline, but this was not appropriate here. There is also the possibility that the standard error of each study estimate was not appropriately accounted for, since the baseline value was incorporated in the SMD and the weighting at each time point; however, removing the weighting from the model made little difference to the findings.

Interpretation

This study confirms our previous findings that placebo response does not seem to have a response-curve and that it persists for at least 12 months [3].

The “longevity” of placebo response has been reported previously [1, 2] and has been interpreted by some authors as regression to the mean [18,19,20]. In this study, we could not investigate whether placebo response was caused by regression to the mean because of the lack of information on the true population mean for the outcome measures. However, regression to the mean could explain many of the characteristics of placebo response, for example, that it tends to be larger for more extreme values and for more unreliable measures. [20].

Using longitudinal analysis showed that outcome type affects not only the magnitude of response in the placebo arm, but also its temporal changes; with the effect on objective outcomes decreasing with time, and the effect on subjective outcomes, including pain, not changing with time and remaining significantly different from baseline values. This is in line with the results of our original paper [3]. Findings in previously published studies, investigating temporal changes in the placebo arm have been inconsistent. Some studies reported that the effect of time is not significant [4] or that trial duration may explain some of the variation in improvement [21]. A meta-analysis of acupuncture trials [2], showed a peak in placebo response at 12 weeks with a subsequent drop at 52 weeks; however, the follow-up visits were divided into six groups according to the assessment timing, allowing a different number of trials to contribute to the effect in each group. Kaptchuk et al. [5] reported a continuous reduction in pain over 8 weeks in a sham acupuncture trial; however, they re-applied the treatment throughout the study, and it is known that administering treatment multiple times reinforces the placebo effect [22].

In our meta-analysis, visit number did not have a significant effect on the magnitude of placebo response. This contradicts the findings of Vase et al., who reported that a larger number of face-to-face visits was associated with a larger placebo response [23]. However, Vase et al. used individual patient data from several pharmacological trials, in which a placebo was administered multiple times during the trial, whereas we analyzed trial-level data from surgical trials, which tend to involve a “one-off” intervention.

Some of the improvement in the placebo arm might have been related to the effect of concomitant treatment. One plausible explanation for improvement is the use of rescue medications, such as pain-killers, or the introduction of lifestyle modifications, such as diet. Another possible explanation is that patients who were allowed to continue their standard pharmacological treatments throughout the trial might have improved due to better adherence to these treatments when in the trial.

Implications

There are two main implications of this study. First, for the researchers and clinicians designing placebo-controlled trials of invasive procedures using subjective outcomes, it is useful to know that the effect in the placebo arm does not seem to change significantly with time. This is important because in a placebo-controlled trial treatment effect is measured as the difference between the change in the active and placebo arms. Second, patients report significant improvement for a prolonged period of time after a single surgical placebo intervention, i.e., a procedure chosen to have no active therapeutic effect. Therefore, surgeons and therapists should be aware that large and sustained improvement in subjective outcomes after a procedure does not always mean that the crucial surgical element of the treatment is effective.