Nocebo effects are stronger and more persistent than placebo effects in healthy individuals
- Department of Neurology, Center for Translational Neuro- and Behavioral Sciences (C-TNBS), University Medicine Essen, University Duisburg-Essen, Germany
- Wellcome Centre for Integrative Neuroimaging (WIN), Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital, United Kingdom
Figures
Figure 1
Study and trial design.
(A) Study design: on day 1, participants underwent a conditioning procedure in which a noxious heat was applied directly after a (sham) TENS: (transcutaneous electric nerve stimulation) stimulation in three conditions. In the placebo condition (PLC), the thermal stimulation was lowered to VAS 40, in the nocebo condition (NOC), it was increased to VAS 80 and in the control condition (CTR) it remained unchanged (VAS 60). During the two tests on days 1 and 8, the same moderate stimulation intensity of VAS 60 was applied in all three conditions. (B) Position of the electrode on the inner lower left arm for (sham) TENS stimulation (approximately 2.5 cm above the wrist) and the thermode at three possible locations (approximately 3.5 cm above the electrode with a distance of 0.5 cm between each of the three locations). (C) Trial design: following the presentation of a visual cue to indicate the condition (e.g. green cross for the placebo condition), first the sham TENS stimulation and then the heat stimulus were applied before participants rated the pain intensity on a 0-100 visual analogue scale.
Figure 2
Pain intensity ratings and placebo and nocebo effects during calibration and test sessions.
(A) Mean pain intensity ratings in the placebo, nocebo, and control condition during calibration, and during the test sessions at days 1 and 8. (B) Placebo effect (control condition – placebo condition, i.e. positive value of difference) and nocebo effect (nocebo condition – control condition, i.e. positive value of difference) on days 1 and 8. Black diamond shapes indicate the mean and circles the individual scores. ***P<0.001, **P<0.01, n.s.: non-significant.
Figure 3
Mean and trial-by-trial pain intensity ratings, placebo and nocebo effects during conditioning.
(A) Mean pain intensity ratings of the placebo, nocebo and control condition during conditioning. (B) Placebo effect (control condition – placebo condition, i.e. positive value of difference) and nocebo effect (nocebo condition – control condition, i.e. positive value of difference) during conditioning. (C) Trial-by-trial pain intensity ratings (with confidence intervals) during conditioning. Black diamond shapes indicate the mean and circles the individual scores. ***P<0.001.
Figure 4
Expectancy ratings obtained before conditioning and before the test sessions on days 1 and 8.
Expectations were assessed using the Generic Rating Scale for Previous Treatment Experiences, Treatment Expectations, and Treatment Effects (Rief et al., 2021). The expected pain relief was derived from the item asking how much improvement the participant expected from the treatment on a 10-point Likert scale from 0 (=no improvement) to 10 (=greatest improvement imaginable). Analogously, the expected pain increase (nocebo effect) was taken from the item asking how much worsening of pain they expected from the treatment from 0 (=no worsening) to 10 (=greatest worsening imaginable). Black diamond shapes indicate the mean and circles the individual scores. ***P<0.001, **P<0.01, *P<0.05, n.s.: non-significant.
Appendix 1—figure 1
Trial-by-trial pain intensity rating during the test phases of days 1 and 8.
Tables
Appendix 1—table 1
Results of multiple linear regression analyses with expectations and prior experience as independent variables and placebo effect or nocebo effect as the dependent variable.
| Beta | Std error | t-value | P-value | |
|---|---|---|---|---|
| Day 1: placebo effect | ||||
| Intercept | –2.919 | 3.756 | –0.777 | 0.439 |
| Expected improvement pre-conditioning (GEEE) | –0.517 | 0.736 | –0.702 | 0.485 |
| Conditioning placebo effect (VAS rating) | 0.300 | 0.094 | 3.179 | 0.002** |
| Expected improvement on day 1 (GEEE) | 0.479 | 0.571 | 0.839 | 0.404 |
| Day 1: nocebo effect | ||||
| Intercept | 3.261 | 3.539 | 0.921 | 0.359 |
| Expected worsening pre-conditioning (GEEE) | 0.288 | 0.446 | 0.646 | 0.519 |
| Conditioning nocebo effect (VAS rating) | 0.136 | 0.075 | 1.807 | 0.074 |
| Expected worsening on day 1 (GEEE) | 0.355 | 0.425 | 0.837 | 0.405 |
| Day 8: placebo effect | ||||
| Intercept | 3.531 | 2.478 | 1.425 | 0.157 |
| Expected improvement pre-conditioning (GEEE) | –0.589 | 0.474 | –1.243 | 0.217 |
| Conditioning placebo effect (VAS rating) | 0.083 | 0.066 | 1.244 | 0.217 |
| Expected improvement on day 1 (GEEE) | –0.769 | 0.463 | –1.661 | 0.100 |
| Placebo effect on day 1 (VAS rating) | 0.315 | 0.064 | 4.904 | <0.001*** |
| Expected improvement on day 8 (GEEE) | 1.033 | 0.459 | 2.251 | 0.027* |
| Day 8: nocebo effect | ||||
| Intercept | 1.253 | 3.826 | 0.328 | 0.744 |
| Expected worsening pre-conditioning (GEEE) | 0.187 | 0.513 | 0.364 | 0.716 |
| Conditioning nocebo effect (VAS rating) | 0.144 | 0.083 | 1.732 | 0.087 |
| Expected worsening on day 1 (GEEE) | –0.395 | 0.523 | –0.755 | 0.452 |
| Nocebo effect on day 1 (VAS rating) | 0.272 | 0.110 | 2.482 | 0.015* |
| Expected worsening on day 8 (GEEE) | 0.210 | 0.457 | 0.459 | 0.647 |
-
GEEE, Generic Rating Scale for Previous Treatment Experiences, Treatment Expectations, and Treatment Effect; VAS, visual analogue scale. Rief et al., 2021.
-
***P<0.001, **P<0.01, *P<0.05.
Appendix 1—table 2
Results of multiple linear regression analyses with expectations, prior experience and psychological factors as independent variables and placebo effect or nocebo effect as the dependent variable.
| Beta | Std error | t-value | P-value | |
|---|---|---|---|---|
| Day 1: placebo effect | ||||
| Intercept | 1.294 | 22.168 | ||
| Expected improvement pre-conditioning (GEEE) | –0.531 | 0.750 | –0.708 | 0.481 |
| Conditioning placebo effect (VAS rating) | 0.303 | 0.097 | 3.120 | 0.002** |
| Expected improvement on day 1 (GEEE) | 0.626 | 0.575 | 1.088 | 0.280 |
| Psychological variables: | ||||
| Somatosensory amplification | –0.654 | 0.227 | –2.877 | 0.005** |
| Trait anxiety | 0.042 | 0.334 | 0.126 | 0.900 |
| Trait depression | 0.220 | 0.308 | 0.712 | 0.478 |
| Behavioural inhibition | –1.528 | 3.100 | –0.493 | 0.623 |
| Behavioural activation | 4.922 | 3.299 | 1.492 | 0.139 |
| Pain catastrophising | 0.070 | 0.136 | 0.511 | 0.611 |
| Experimenter warmth | –4.161 | 3.027 | –1.375 | 0.173 |
| Experimenter competence | 4.732 | 3.742 | 1.265 | 0.209 |
| Day 1: nocebo effect | ||||
| Intercept | –36.384 | 15.752 | –2.310 | 0.023 |
| Expected worsening pre-conditioning (GEEE) | 0.402 | 0.470 | 0.856 | 0.394 |
| Conditioning nocebo effect (VAS rating) | 0.131 | 0.078 | 1.690 | 0.095 |
| Expected worsening on day 1 (GEEE) | 0.200 | 0.442 | 0.454 | 0.651 |
| Psychological variables: | ||||
| Somatosensory amplification | –0.206 | 0.167 | –1.235 | 0.220 |
| Trait anxiety | 0.445 | 0.255 | 1.745 | 0.084 |
| Trait depression | –0.096 | 0.225 | –0.425 | 0.672 |
| Behavioural inhibition | 4.011 | 2.312 | 1.735 | 0.086 |
| Behavioural activation | 4.800 | 2.416 | 1.987 | 0.050 |
| Pain catastrophising | 0.084 | 0.098 | 0.857 | 0.394 |
| Experimenter warmth | –0.352 | 2.314 | –0.152 | 0.879 |
| Experimenter competence | 5.791 | 2.801 | 2.067 | 0.042* |
| Day 8: placebo effect | ||||
| Intercept | 17.843 | 14.498 | 1.231 | 0.222 |
| Expected improvement pre-conditioning (GEEE) | –0.702 | 0.496 | –1.417 | 0.160 |
| Conditioning placebo effect (VAS rating) | 0.063 | 0.073 | 0.863 | 0.391 |
| Expected improvement on day 1 (GEEE) | –0.949 | 0.507 | –1.872 | 0.065 |
| Placebo effect on day 1 (VAS rating) | 0.382 | 0.071 | 5.343 | <0.001*** |
| Expected improvement on day 8 (GEEE) | 1.131 | 0.536 | 2.110 | 0.038* |
| Psychological variables: | ||||
| Somatosensory amplification | 0.233 | 0.167 | 1.396 | 0.167 |
| Trait anxiety | –0.215 | 0.227 | –0.948 | 0.346 |
| Trait depression | –0.217 | 0.218 | –0.995 | 0.323 |
| Behavioural inhibition | –1.344 | 2.051 | –0.655 | 0.514 |
| Behavioural activation | –1.166 | 2.232 | –0.522 | 0.603 |
| Pain catastrophising | –0.129 | 0.092 | –1.403 | 0.165 |
| Experimenter warmth | –0.727 | 2.059 | –0.353 | 0.725 |
| Experimenter competence | –0.563 | 2.499 | –0.225 | 0.822 |
| Day 8: nocebo effect | ||||
| Intercept | –9.215 | 17.887 | –0.515 | 0.608 |
| Expected worsening pre-conditioning (GEEE) | 0.650 | 0.580 | 1.122 | 0.265 |
| Conditioning nocebo effect (VAS rating) | 0.103 | 0.092 | 1.119 | 0.267 |
| Expected worsening on day 1 (GEEE) | –0.325 | 0.565 | –0.574 | 0.567 |
| Nocebo effect on day 1 (VAS rating) | 0.290 | 0.124 | 2.349 | 0.021* |
| Expected worsening on day 8 (GEEE) | –0.154 | 0.516 | –0.298 | 0.766 |
| Psychological variables: | ||||
| Somatosensory amplification | –0.080 | 0.199 | –0.403 | 0.688 |
| Trait anxiety | 0.099 | 0.288 | 0.345 | 0.731 |
| Trait depression | 0.093 | 0.261 | 0.356 | 0.723 |
| Behavioural inhibition | 1.759 | 2.600 | 0.677 | 0.501 |
| Behavioural activation | –1.615 | 2.861 | –0.565 | 0.574 |
| Pain catastrophising | 0.064 | 0.110 | 0.576 | 0.566 |
| Experimenter warmth | 2.569 | 2.687 | 0.956 | 0.342 |
| Experimenter competence | –0.608 | 3.190 | –0.191 | 0.849 |
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GEEE, Generic Rating Scale for Previous Treatment Experiences, Treatment Expectations, and Treatment Effect, VAS, visual analogue scale. Rief et al., 2021
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***P<0.001, **P<0.01, *P<0.05.
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Nocebo effects are stronger and more persistent than placebo effects in healthy individuals
eLife 14:RP105753.
https://doi.org/10.7554/eLife.105753.3
