![Session 2 fMRI results. Side effects lead to larger pain relief and are associated with increased rACC-PAG coupling. A) The expectation group continued to show lower pain ratings after active placebo compared to inert placebo, while the no-expectation group did not show this difference any more (p=0.04; VAS 38.7±3.4 vs 43.0±3.2 and VAS 45.0±3.3 vs 43.5±3.3);. B) Side effects continued to be experienced after active placebo with no difference between groups (p<0.001; 2.71±0.58 vs 0.05±0.22). C) We observed reduced BOLD signal during active placebo in the rACC (T=4.5, p=0.003; [[activeexp < inertexp] > [activeno-exp < inertno-exp]]). D) RACC-PAG coupling was increased during active placebo (T=4.37, p<0.001 [[activeexp > inertexp] > [activeno-exp > inertno-exp]]), indicating a stronger recruitment of the descending pain modulatory](https://www.researchgate.net/publication/375860375/figure/fig3/AS:11431281206565279@1700768391903/Session-2-fMRI-results-Side-effects-lead-to-larger-pain-relief-and-are-associated-with_Q320.jpg)
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How side effects can improve treatment efficacy: a
randomized trial
Lieven A. Schenk1* Ph.D., Tahmine Fadai1 M.D., Christian Büchel1 M.D.
1 Department of Systems Neuroscience, University Medical Center Hamburg-Eppendorf,
Hamburg, Germany
*Corresponding author:
Lieven A. Schenk
Department of Systems Neuroscience, University Medical Center Hamburg-Eppendorf, Hamburg,
Germany
li.schenk@uke.de
Clinical Trials Registration: https://drks.de/search/de/trial/DRKS00026648
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NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice.
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Abstract
While treatment side effects may adversely impact patients, they could also potentially function as
indicators for effective treatment. In this study, we investigated whether and how side effects can
trigger positive treatment expectations and enhance treatment outcomes.
In this preregistered trial (DRKS00026648), 77 healthy participants were made to believe that they
will receive fentanyl nasal sprays before receiving thermal pain in a controlled experimental
setting. However, nasal sprays did not contain fentanyl, rather they either contained capsaicin to
induce a side effect (mild burning sensation) or saline (control). Following the initial phase,
participants were randomized to two groups and underwent functional magnetic resonance
imaging (fMRI). One group continued to believe that the nasal sprays could contain fentanyl while
the other group was explicitly informed that no fentanyl was included. This allowed for the
independent manipulation of the side effects and the expectation of pain relief.
Our results revealed that nasal sprays with a side effect lead to lower pain than control nasal sprays
without side effects. The influence of side effects on pain was dependent on individual beliefs
about how side effects are related to treatment outcome, as well as on expectations about received
treatment. FMRI data indicated an involvement of the descending pain modulatory system
including the anterior cingulate cortex and the periaqueductal gray during pain after experiencing
a nasal spray with side effects.
In summary, our data show that mild side effects can serve as a signal for effective treatment
thereby influencing treatment expectations and outcomes, which is mediated by the descending
pain modulatory system. Using these mechanisms in clinical practice could provide an efficient
way to optimize treatment outcome. In addition, our results indicate an important confound in
clinical trials, where a treatment (with potential side effects) is compared to placebo.
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Keywords: side effect, non-specific treatment factor, active placebo, treatment expectation,
placebo analgesia, fMRI
Introduction
Common thinking in modern medicine posits that ideal treatments should have no side effects,
because they can cause discomfort, suffering and treatment discontinuation. In addition, the mere
expectation of side effects increases the likelihood of side effects1. Consequently, it has been
suggested to not only minimize side effects, but also to carefully disclose information regarding
potential side effects to avoid these nocebo effects2.
Here we challenge this view and ask whether some side effects could actually lead to better
treatment outcomes. This idea is motivated by the observation that side effects themselves can
contribute to treatment expectations3. Our hypothesis posits that even mild side effects can be
indirect indicators of treatment potency (e.g. side effects are unavoidable with a powerful drug),
which can lead to positive treatment expectations. These treatment expectations are the basis for
non-specific therapeutic effects (i.e. placebo effect) that have substantial impact on treatment
outcomes4–6.
Support for this hypothesis comes from research on active placebos, i.e. pharmacological agents
that have a noticeable effect on the patient but not on the primary symptoms. A previous study on
pain suggested that active placebos can indeed lead to larger placebo effects than inert placebos7.
This idea also resonates with the observation that general practitioners prescribed more impure
(i.e. active) placebos than inert placebos8.
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The question of whether side effects can influence treatment outcome is also relevant for
randomized clinical trials, as most studies compare active pharmacological interventions with inert
placebos9. If the experience of side effects can indirectly boost treatment outcome, a clinical trial
might overestimate the beneficial effect of active treatments that have an easily identifiable side
effect profile.
To address these questions, we designed a multistep experiment to investigate how side effects
influence treatment efficacy on the psychological and neural level in a large sample of healthy
volunteers using fMRI (Figure 1). The study was done in a controlled experimental placebo
paradigm to exclude hidden pharmacological effects and isolate psychological and neural
mechanisms, therefore it is not related to any drug-specific pharmacological effects and can be
generalized to other treatments. According to our preregistration
(https://drks.de/search/de/trial/DRKS00026648), we hypothesized that side effects act as a cue for
effective treatment and influence pain and placebo effects by augmenting expectation mechanisms.
With respect to neuronal effects we hypothesized that side effects would recruit the descending
pain modulatory system and in particular that the coupling between the rostral ACC and the PAG
is modulated.
Materials and Methods:
Participants
104 healthy participants were enrolled in this study. Nine participants were excluded due to
problems with the nasal spray, one due to a technical problem and two due to floor effects of
applied pain (mean ratings < VAS10). 15 participants were excluded after performing the
preregistered manipulation check (see Supplementary Information). 77 participants were included
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in the data analysis (42 expectancy group (age: 24.3±3.8 [18-38], 12 male); 35 no-expectancy
group (age: 24.8±5.4 [18-43], 14 male)). Participants were confirmed to be healthy with an in-
person interview with a medical doctor during the initial visit (see Supplementary Information).
All participants gave written consent according the Declaration of Helsinki and the study was
approved by the Ethics Committee of the Hamburg Medical Association.
Figure 1: Experimental Design. In the first session, participants received three different nasal
sprays (in three separate runs) with the information that each of them could contain the potent pain
killer fentanyl. Unbeknownst to the participants, none of the nasal sprays contained any active pain
medication, but one of the nasal sprays contained a small dose of capsaicin, causing a mild, but
clearly perceptible burning-like sensation in the nose. After the application of the nasal sprays, a
series of thermal pain stimuli was applied (corresponding to previously calibrated levels of 40, 60
or 70 on a visual analogue scale (VAS) from 0 to 100) and participants rated their pain on the
VAS. Pain was reduced in the placebo conditions to mimic a treatment benefit. In a similar second
session, the same procedure was repeated during fMRI to investigate the neural mechanisms of
how side effects can modulate treatment efficacy. To test for the role of expectation of treatment
benefit, the sample was randomized into two groups before the second session. The expectation
group believed that the experiment will be repeated and continued to expect that any pain decreases
were due to the pain relieving fentanyl nasal spray, whereas the no-expectation group was
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explicitly debriefed that no fentanyl was present in any nasal spray and that all differences in pain
were due to differences in the applied temperature. Therefore, side effects and expectation of
treatment benefit were manipulated in an independent fashion, which allowed us to not only
investigate the role of side effects and expectation, but also the interaction between both factors.
Experimental paradigm
The experiment consisted of 3 visits. During the initial visit, participants were informed about the
research, checked for eligibility, and signed consent forms. Participants underwent a medical
counseling session were they received information that the aim of the study was to investigate
the neural processes associated with fentanyl nasal spray, a powerful analgesic drug used in the
treatment of cancer pain. They were informed about the medication’s purpose and potential side
effects of fentanyl, which included a burning sensation in the nose. Afterwards, basic vital
information (height, weight, blood pressure) was assessed and a drug screening was performed.
Participants then completed a series of questionnaires, including questions about their belief that
side effects indicate a more potent treatment.
During the experimental visit, critical instructions were repeated and a heat pain sensitivity
assessment was performed. Heat pain stimuli were applied using a thermode (PATHWAY System,
Medoc, Ramat Yishai, Israel). Participants were then instructed how to use a visual analogue scale
(VAS) to rate their pain (ranging from 0=no pain to 100=maximum tolerable pain). Finally,
participants rated the intensity of a series of painful heat stimuli to establish temperature levels
corresponding to individual pain at VAS 40, 60 and 70.
During the experiment, participants believed that they receive three nasal sprays in three
experimental runs, each with a 50% chance of containing fentanyl, and that this procedure will be
repeated in the MR scanner as well as 7±1 days later (Figure 1). Unbeknownst to the participants,
none of the nasal sprays contained any fentanyl. However, one of the three nasal sprays (applied
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second or last) contained a small dose of capsaicin (0,15 μg/puff), which causes a burning
sensation in the nose. After the application of each nasal spray, participants had to rate several
items regarding potential side effects on a 4-point scale (“none at all”, “minimally”, “a bit”,
“clearly”), including experiencing a burning sensation in the nose. Before each run, the thermode
was moved to avoid sensitization or habituation and three warm-up stimuli were applied (20s).
Each run consisted of 24 trials, and each trial consisted of anticipation (1.5s-2.5s), pain stimulation
(6.5s with 4s pain plateau), VAS pain rating (8s) and a variable inter-trial-interval (7-9s).
The difference between the runs was the potential side effect experience (capsaicin or no capsaicin)
and the applied temperature (VAS 40, 60 or 70; Figure 1). The first nasal spray always
corresponded to the sham control condition. During this condition, the nasal spray did not cause
any side effects (saline, no capsaicin) and pain corresponded to VAS 70. During the following two
runs, participants received reduced pain corresponding to VAS 40 with either a saline nasal spray
with capsaicin (active placebo) or without capsaicin (inert placebo). Stimulation temperature was
reduced in both placebo conditions to mimic a treatment benefit compared to the previous sham
control run. Both runs were the conditions of interest and the order was randomized across
participants and concealed to participants and experimenters.. Afterwards, participants answered
questions regarding their expectation of what they received in the previous runs and on how sure
they were about their answer.
After the three runs, but before the MRI measurements, volunteers were randomized into an
expectation and a no-expectation group. The randomized group allocation for all participants was
performed at the start of data collection using a custom MATLAB script. The no-expectation group
was debriefed to eliminate their expectation of pain relief, similar to previous experiments10. They
were told that no fentanyl was present in any of the nasal sprays and that the pain was
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surreptitiously reduced during the second and third run. The expectation group was not informed
and simply received the instruction that the same procedure will be repeated in the MR scanner.
During MR scanning, participants completed the same paradigm as before, with the exception that
during the second and third run they received pain corresponding to VAS 60. Participants were
taken out of the scanner between runs and moved into a seating position to apply the nasal sprays,
so that they could see that the same nasal sprays were applied. Finally, participants were invited
for a follow-up visit (see Supplementary Information). At the end of the experiment, the
expectation group was also debriefed. To account for the deceptive component, we reinstated
participants’ autonomy by explicitly asking them whether they would like to withdraw their data
at this stage. However, none of the participants withheld their approval.
Behavioral data analysis
Behavioral data analysis was performed using SPSS 27 (IBM, Armonk, USA). Pain rating data
were analyzed using repeated measures ANOVAs with condition (within) and group (between) as
predictors and pain ratings as dependent variables, separate for each phase. For within-subject
contrasts, paired-T-test and Wilcoxon Signed-Ranks Test were used, depending on scale and
normal distribution. Multiple comparisons were Bonferroni-corrected. For mediation analysis,
differences (active – inert) were calculated for side effects, treatment expectations (with guess
treatment=2, no guess=1, guess control=0) and pain rating. The belief of how side effects influence
treatment was assessed with their agreement (1-5) with the question: “stronger treatments have
more side effects”. Mediation analysis was then performed with PROCESS in SPSS (model 8)
with 5000 bootstrap samples to test for significance. All effects were considered significant at
P<0.05 (two tailed).
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fMRI data analysis
fMRI data preprocessing and statistical analyses were performed using SPM12 (Wellcome
Department of Imaging Neuroscience, London, UK). Data preprocessing consisted of slice timing,
motion correction and coregistration of the functional images to the T1 anatomical scan. Finally,
the images were spatially normalized using DARTEL (based on the IXI555 template from the
CAT12 toolbox, http://dbm.neuro.uni-jena.de/cat/) and smoothed using a 6-mm (FWHM)
isotropic Gaussian kernel.
We performed a first level analysis using a general linear model in SPM12. Each regressor was
modeled by boxcar functions convolved with a canonical hemodynamic response function (HRF).
For each run, we included regressors for cue, pain and pain rating. T-contrasts of interest were then
calculated. T-tests between conditions of interest were used to test for significance. To maximize
power, we employed a ROI approach according to our preregistration and selected ROIs based on
previous meta-analyses: rostral ACC (interaction/inert contrast, 10mm)11; DLPFC
(interaction/inert contrast, 10mm)11; insula (inert contrast, 8mm)11; S2 (inert contrast, 8mm)11 and
PAG (inert contrast/connectivity analysis, 4mm)12. For medial regions (rostral ACC and the PAG),
one ROI (with x=0) was used. For each contrast of interest, all ROIs were combined into a single
mask to avoid inflation of Type-I Error. Results were considered significant at p<0.05 FWE
corrected.
To test for a modulation of coupling between the rACC and the PAG, we performed a Psycho-
Physiological Interaction (PPI) analysis13. We extracted the time series within a 3 mm sphere
around the peak activation of the rACC from the interaction contrast [-6 33 -1.5] during the pain
phase. Then we calculated the PPI interaction term as the time series multiplied by the
psychological predictor (pain vs no pain). All three regressors were subsequently included in a
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new first level analysis. After model estimation, t-contrasts of interest were calculated for the PPI
interaction, and PAG modulation was investigated with a ROIs of 4mm radius12.
For illustration purposes, all statistical maps use a significance threshold of p < 0.005 uncorrected
and were overlaid on the mean structural image of all participants. All activations are reported
using x, y, z coordinates in MNI (Montreal Neurological Institute) standard space.
Results
Side effects lead to improved pain relief and are mediated by treatment expectations
For the first session, we established that participants experienced more side effects after active
placebo (p<0.001; F(1,75)=1138; Figure 2A). No interaction (p=0.65) or main effect of group
(p=0.89) was observed. While all participants expected pain relief from the nasal sprays, we
observed that pain ratings were lower after active placebo as compared to inert placebo (p=0.002;
F(1,75)=10.7; VAS 26.2±2.0 vs 30.2±2.0; Figure 2B; Figure S1). As expected, there was no
interaction (p=0.60) and no main effect of group (p=0.33). This clearly shows that the experience
of side effects caused more pronounced pain relief.
When asked to rate whether they believe that a nasal spray contained fentanyl or not (Figure 2C),
most participants believed that the active placebo condition contained fentanyl (94.8%). Contrary
to this, the inert placebo condition was more ambiguous and only a minority of participants
believed that it contained fentanyl (16.9%, p<0.001). Consistently, the confidence in their rating
was larger in the active placebo condition compared to the inert placebo condition (p<0.001; Figure
S2).
In a next step, we tested whether the effect of side effects depended on the participants’
expectations of having received treatment or control, as well as on their belief that side effects
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indicate a more potent treatment (see preregistration). We therefore conducted a moderated
mediation analysis to test whether their belief that side effects indicate a more potent treatment
moderated the effect of side effects on treatment expectation and if their expectation about having
received fentanyl or control mediated the relationship between experienced side effects and pain
relief. We observed a full moderated mediation (indirect path: -1.57(0.88); 95%CI: [-3.83 -0.44];
Figure 2D), indicating that side effects did not directly influence pain relief, but that side effects,
depending on their belief about how side effects affect treatments, influence their expectations
about their treatment and that these, in turn, influenced pain relief.
Figure 2: Session 1 Results. Side effects lead to larger pain relief and are mediated by
treatment expectations. A) Participants experienced more side effects after active placebo
compared to inert placebo (p<0.001; 2.74±0.59 vs 0.13±0.38). B) Pain ratings were lower after
active placebo as compared to inert placebo (p=0.002; VAS 26.2±2.0 vs 30.2±2.0), showing that
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the experience of side effects influenced pain relief. C) Most participants rated the sham condition
as control (control: 93.5%; no expectation: 3.9%; fentanyl: 2.6%). The active placebo condition
was believed to contain fentanyl by nearly all participants (fentanyl: 94.8%; control: 5.2%). The
inert placebo condition was the most ambiguous condition: Even though participants experienced
pain relief in comparison to the sham condition, more than 83% did not believe that the nasal spray
contained any medication (control: 75.3%; fentanyl: 16.9%; no expectation: 7.8%). All conditions
were rated significantly different from each other (all comparisons p<0.001). D) While their belief
that side effects indicate a more effective treatment moderated the relationship between
experienced side effects and their treatment expectations, , the expectation about their received
treatment mediated the relationship between the experienced side effects and pain relief (indirect
path: -1.57(0.88); lower 95%CI: -3.83; upper 95%CI: -0.44).
Side effects lead to improved pain relief and are associated with increased rACC-PAG
coupling
During the following MR session, participants were randomly allocated into an expectation group
that continued to believe that pain decreases were due to fentanyl, and a no-expectation group that
was explicitly debriefed that no fentanyl was present. We observed a significant interaction
between expectation and side effects: The expectation group continued to show lower pain ratings
after active placebo compared to inert placebo, while the no-expectation group did not show this
difference any more (p=0.04; F(1,75)=4.3; Figure 3A; Figure S1). We did not observe a main
effect of side effect (p=0.31) and no main effect of group (p=0.45). Side effects continued to be
experienced after active placebo (p<0.001; F(1,75)=1305; Figure 3B, Figure S3) with no group
difference (p=0.44) or interaction (p=0.50). This further supports the observation that pain relief
is larger after experiencing a side effect and shows that this effect is modulated by the expectation
of pain relief by a treatment, thereby further supporting that side effects lead to larger pain relief
when treatment benefit is expected.
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We also reinvited participants to repeat the experiment 7±1 days later. As in the first session, we
again observed a main effect of side effect, with lower pain ratings for the active placebo as
compared to the inert placebos (p=0.004; F(1,65)=9.0). However, the group difference was not
significant (p=0.15) and there was no interaction effect (p=0.93) anymore. This shows that after
7±1 days, without any further expectation manipulation, active placebo continued to lead to larger
pain relief. Interestingly, the debriefed no-expectation group reestablished their expectation of
treatment benefit (Figure S4).
To investigate the neural basis of how side effects interact with treatment expectations, we used
fMRI to test for BOLD differences during pain stimulation. We expected that increased pain relief
due to side effects might be mediated by a stronger activation of the descending pain modulatory
system. Based on previous studies14–16, we therefore preregistered the hypothesis that the side
effect by expectation interaction will be associated with a modulation of the rostral anterior
cingulate cortex (rACC), the dorsolateral prefrontal cortex (DLPFC), as well as a modulation of
the coupling between the rACC and the periaqueductal gray (PAG). Testing for the interaction, we
observed a modulation of the rACC (T=4.5, p=0.003, [-6 33 -1.5]; Figure 3C) in the reverse
contrast, indicating a reduced BOLD signal during active placebo in the expectation group, similar
to previous work15. We did not observe a modulation of the DLPFC. We then tested if the coupling
between the rACC and the PAG is increased during active vs inert placebo in the expectation group
compared to the no-expectation group. We observed a significantly increased coupling (T=4.37,
p<0.001, [0 -30 -12]; Figure 3D), indicating a stronger activation of the descending pain
modulatory network during active placebo17.
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Figure 3: Session 2 fMRI results. Side effects lead to larger pain relief and are associated
with increased rACC-PAG coupling. A) The expectation group continued to show lower pain
ratings after active placebo compared to inert placebo, while the no-expectation group did not
show this difference any more (p=0.04; VAS 38.7±3.4 vs 43.0±3.2 and VAS 45.0±3.3 vs
43.5±3.3);. B) Side effects continued to be experienced after active placebo with no difference
between groups (p<0.001; 2.71±0.58 vs 0.05±0.22). C) We observed reduced BOLD signal during
active placebo in the rACC (T=4.5, p=0.003; [[activeexp < inertexp] > [activeno-exp < inertno-exp]]). D)
RACC-PAG coupling was increased during active placebo (T=4.37, p<0.001 [[activeexp > inertexp]
> [activeno-exp > inertno-exp]]), indicating a stronger recruitment of the descending pain modulatory
system.
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Discussion
In this study, we show that side effects can improve pain relief through the amplification of
treatment expectations. We also show that expectations about treatments mediate the effect of side
effects on pain relief and that this is dependent on participants’ individual beliefs of how side
effects are related to treatments. Additionally, our fMRI results indicate that pain relief induced by
active placebos involve a recruitment of the descending pain modulatory system.
Our data show that side effects do not directly act on the pain experience, but are mediated by
treatment expectations, and are dependent on beliefs of how side effects are related to treatment
effectiveness. This is in line with placebo research that shows that contextual factors primarily
influence expectations that then in turn influence treatment outcome10. Therefore, if these
mediating beliefs can be changed, treatment providers can influence how side effects affect
treatment outcome.
We observed a modulation of the rACC and a stronger rACC-PAG coupling when side effects
boost pain relief. Previous research with fMRI18, or molecular imaging19 has implicated this
pathway in treatment expectation induced pain relief and descending pain modulation.
Furthermore, rACC-PAG connectivity correlates with pain relief15 and blocking µ-opioid
receptors with naloxone can abolish both rACC-PAG coupling and expectation induced pain
relief15. Therefore, our results indicate that the increased expectation of treatment benefits that
arise from the experience of side effects also recruits the descending pain modulatory system.
In contrast to our hypothesis, we did not observe a modulation of the DLPFC. Although the DLPFC
is implicated in placebo analgesia in several studies16, our non-significant result with respect to
the DLPFC is in line with a recent meta-analysis with individual participant data20, that could not
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confirm a significant effect in the DLPFC, possibly related to a large variability of the effect across
individuals.
One additional aspect to consider is whether our effects are the result of conditioned pain
modulation (CPM)21. In CPM a tonic painful stimulus (i.e. nasal capsaicin) renders a phasic painful
stimulus (i.e. thermal pain) at a different body site less painful. However, CPM is unlikely to be
relevant for our findings for two reasons: The very small dose of capsaicin inducing a mild burning
sensation, as would be expected to occur as a normal treatment side effect, is unlikely to be
sufficiently intense to induce CPM based on previous studies showing that a high intensity tonic
stimulus is required for CPM22. More importantly, our observed interaction during session 2
(Figure 3A) cannot be explained by CPM as in both groups the burning sensation in the nose is
identical.
Our study has also two major clinical implications. Using strategies to maximize positive treatment
expectancies (i.e. placebo effects) in clinical practice can significantly improve many treatment
outcomes4,5,23. Our data suggests that mild and benign side effects do not necessarily have to be
harmful to patients and could potentially even resemble an overall benefit for treatment outcome.
One could even think of artificially changing the formulation of established drug to include mild
side effects to increase treatment expectations. However, while research on open label placebo24
provides the idea that this effect could be used without deception, great care would be necessary
to avoid any unintended harm.
A simpler strategy to increase treatment benefit may lie in the framing of side effects25. Current
expert consensus on how to inform patients about side effects emphasize the prevention of nocebo
effects26. Studies show that optimized communication such as positive framing of side effects can
indeed reduce nocebo effects2,27. Our mediation analysis shows that the effect of side effects on
. CC-BY-NC-ND 4.0 International licenseIt is made available under a
is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.(which was not certified by peer review)preprint The copyright holder for thisthis version posted November 22, 2023. ; https://doi.org/10.1101/2023.11.22.23298877doi: medRxiv preprint
17
pain relief depends on beliefs that side effects are a sign of treatment effectiveness. Therefore,
optimized framing of side effects as a cue that the treatment is acting and healing might not only
reduce nocebo effects but also increase positive treatment expectations and placebo effects, which
often lead to more beneficial treatment outcomes4,5,28. Our data also supports the idea that this
information can be conveyed without inducing additional nocebo effects (see Supplementary
Figure S3). Therefore, our study shows the psychological and neural mechanism that could be used
to achieve this improvement in framing of side effects, however, it would be important to replicate
the effect in a clinical sample.
Our study also has important implications for the interpretation of placebo controlled randomized
clinical trials. Methodological standards such as random treatment allocation, double-blinding of
patient and providers, and others have been established to achieve the assumption that nonspecific
factors (i.e. placebo effects) are additive between the different experimental conditions and
therefore the treatment effect can be isolated29. As our treatment allocation instruction was
probabilistic as in most clinical trials, we can extend our findings to clinical trials and show that
side effects can have a major effect on the expectations of having received treatment or having
received control, consistent with previous findings30,31. Here, we also show that these treatment
expectations then lead to differences in placebo effect. Our data supports that side effects can
differentially influence placebo effects when side effect occurrence differs between experimental
conditions, as is often the case in clinical trials32,33. The validity of clinical trials depends on the
additivity of nonspecific factors (i.e. placebo effect). Our data shows that this is not the case if side
effects differ between treatment and control arm and therefore question the validity of the
additivity assumption in these cases. As a consequence, clinical trials could overestimate the effect
of a drug if side effects increase placebo effects in the treatment condition. Active placebos in the
. CC-BY-NC-ND 4.0 International licenseIt is made available under a
is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.(which was not certified by peer review)preprint The copyright holder for thisthis version posted November 22, 2023. ; https://doi.org/10.1101/2023.11.22.23298877doi: medRxiv preprint
18
control arm9 or other innovative research designs34 could counteract this confounds and improve
clinical trial validity. Taken together, our data shows the significant influence of side effects on
treatment expectations and placebo effects. Taking these effects into account could improve
clinical practice as well as clinical trials.
Data availability statement: All non-identifiable data produced in the present study are available
upon reasonable request to the authors.
Acknowledgements: We would like to thank Daniel Rathmann, Nora Kösters and Justus
Lübbemeier for their dedicated support during data collection. We also thank Björn Horing for
administrative support during funding acquisition as well as Ulrike Bingel and Winfried Rief for
comments on an earlier version of this manuscript.
Funding: L.S., T.F. and C.B. were supported by DFG SFB 289 Project A02 (Project-ID
422744262–TRR 289). C.B was supported by ERC-AdG-883892-PainPersist.
Competing interests: The authors declare no competing interests.
Author contributions: Conceptualization, methodology, investigation, data curation, formal
analysis, visualization, project administration, writing – original draft, L.S.; Methodology,
investigation, validation, writing – review and editing T.F.; Conceptualization, methodology,
resources, funding acquisition, supervision, validation, project administration, writing – review
and editing, C.B.
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is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.(which was not certified by peer review)preprint The copyright holder for thisthis version posted November 22, 2023. ; https://doi.org/10.1101/2023.11.22.23298877doi: medRxiv preprint
19
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