Counterconditioning as Treatment to Reduce Nocebo Effects in Persistent Physical Symptoms: Treatment Protocol and Study Design

Abstract

Persistent physical symptoms have a high prevalence and a large impact for patients and society. To date, treatment effects for these symptoms are often limited. Nocebo effects (i.e., negative outcomes that are not attributable to active treatment components) have a substantial influence on treatment success and can be established via learning through classical conditioning. Therefore, interventions aimed at reducing nocebo effects by means of counterconditioning, in which an alternative association (inhibiting the previous association) is learned, could be a promising method for improving physical symptoms. In experimental studies, counterconditioning has been shown promising in reducing experimentally-induced nocebo effects on pain and itch. Application of counterconditioning procedures to reduce nocebo effects on clinical symptoms has yet to be researched. This paper provides a protocol of a 6-week counterconditioning intervention aimed at reducing nocebo effects and clinical pain in patients with fibromyalgia. A study in patients with fibromyalgia is proposed to examine the feasibility and potential effectiveness of this counterconditioning intervention as a novel treatment method for reducing nocebo effects and generalization to clinical pain symptoms. Results can help design an optimized treatment protocol for reducing nocebo effects, based on the experiences of participants and the first indications of treatment efficacy.

Full text

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STUDY PROTOCOL
published: 13 June 2022
doi: 10.3389/fpsyg.2022.806409
Edited by:
Luana Colloca,
University of Maryland, Baltimore,
United States
Reviewed by:
Harald C. Traue,
University of Ulm, Germany
Franziska Labrenz,
Ruhr-University Bochum, Germany
*Correspondence:
Simone Meijer
s.meijer@fsw.leidenuniv.nl
Specialty section:
This article was submitted to
Neuropsychology,
a section of the journal
Frontiers in Psychology
Received: 31 October 2021
Accepted: 17 May 2022
Published: 13 June 2022
Citation:
Meijer S, van Middendorp H,
Peerdeman KJ and Evers AWM
(2022) Counterconditioning as
Treatment to Reduce Nocebo Effects
in Persistent Physical Symptoms:
Treatment Protocol and Study Design.
Front. Psychol. 13:806409.
doi: 10.3389/fpsyg.2022.806409
Counterconditioning as Treatment to
Reduce Nocebo Effects in Persistent
Physical Symptoms: Treatment
Protocol and Study Design
Simone Meijer1,2*, Henriët van Middendorp1,2 , Kaya J. Peerdeman1,2 and
Andrea W. M. Evers1,2,3,4
1Health, Medical and Neuropsychology Unit, Leiden University, Leiden, Netherlands, 2Leiden Institute for Brain
and Cognition, Leiden, Netherlands, 3Department of Psychiatry, Leiden University Medical Center, Leiden, Netherlands,
4Medical Delta Healthy Society, Leiden University, Technical University Delft, & Erasmus University Rotterdam, Leiden,
Netherlands
Persistent physical symptoms have a high prevalence and a large impact for patients
and society. To date, treatment effects for these symptoms are often limited. Nocebo
effects (i.e., negative outcomes that are not attributable to active treatment components)
have a substantial influence on treatment success and can be established via learning
through classical conditioning. Therefore, interventions aimed at reducing nocebo
effects by means of counterconditioning, in which an alternative association (inhibiting
the previous association) is learned, could be a promising method for improving physical
symptoms. In experimental studies, counterconditioning has been shown promising
in reducing experimentally-induced nocebo effects on pain and itch. Application of
counterconditioning procedures to reduce nocebo effects on clinical symptoms has
yet to be researched. This paper provides a protocol of a 6-week counterconditioning
intervention aimed at reducing nocebo effects and clinical pain in patients with
fibromyalgia. A study in patients with fibromyalgia is proposed to examine the feasibility
and potential effectiveness of this counterconditioning intervention as a novel treatment
method for reducing nocebo effects and generalization to clinical pain symptoms.
Results can help design an optimized treatment protocol for reducing nocebo effects,
based on the experiences of participants and the first indications of treatment efficacy.
Keywords: nocebo effects, counterconditioning, persistent physical symptoms, open-label, classical
conditioning
INTRODUCTION
Persistent physical symptoms have a high prevalence and a large impact for patients and society. To
date, treatment of these symptoms is effective to a limited extent. Potentially, targeting placebo and
nocebo effects (i.e., positive and negative treatment outcomes not attributable to active treatment
components, respectively) could provide a novel pathway to prevent or decrease persistent physical
symptoms. Placebo and nocebo effects have consistently been found to affect physical symptoms,
such as pain, in a positive or negative way, respectively (Benedetti et al., 2003;Colloca et al., 2008;
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Vase et al., 2009;Colloca and Finniss, 2012;Bartels et al., 2014;
Colagiuri et al., 2015;Peerdeman et al., 2016;Ba¸bel et al., 2017;
Thomaidou et al., 2020). For example, when patients are told a
certain procedure will cause a stinging pain, they may experience
more pain than when patients are told the procedure will only
feel like a slight pinch. Or, when patients had several treatments
at the hospital causing nausea, they might already start to feel
nauseous upon merely entering the hospital. Because it is not
always possible to prevent such nocebo effects from occurring,
it is relevant to examine the potential effects of treatments aimed
at reducing nocebo effects.
Classical conditioning is an important associative learning
mechanism for the induction of nocebo effects (Bräscher et al.,
2018;Thomaidou et al., 2020). During nocebo conditioning, an
aversive stimulus (unconditioned stimulus, US; e.g., a highly
painful stimulus) leading to an unconditioned response (UR; e.g.,
pain increase) is paired with a neutral stimulus (typically a sham
treatment, such as a sham electrode). Repeated pairing of the two
stimuli during a learning or acquisition phase (e.g., pain stimulus
together with activation of a sham electrode) can lead to the
neutral stimulus (e.g., activation of a sham electrode) becoming
a conditioned stimulus (CS). This CS will elicit a similar response
(conditioned response; CR, i.e., pain increase) as the UR, even
without the US being present. This may also occur in patients
with persistent physical symptoms, especially since they may
have had several negative treatment experiences. For example, if
a person experienced side effects to a certain drug in the past,
they may experience these side effects again while taking another
drug, merely because they were negatively conditioned in the past
(Barsky et al., 2002).
As classical conditioning plays such an important role in the
induction of nocebo effects, methods attenuating conditioned
effects may be promising for reducing nocebo effects. The
attenuation of conditioned effects has been studied more
extensively in the field of fear and evaluative conditioning than
in the field of nocebo research. Conditioned fear responses can
be reduced by extinction, during which the CS is no longer
presented together with the US. Through this, the association
between CS and US decreases, leading to diminishing of the
CR (Vervliet et al., 2013). Furthermore, exposure therapy, which
is based on the principles of extinction learning by exposing
people to fearful situations in a safe way without anything bad
happening to them, can effectively treat fear responses (e.g.,
spider phobia). Exposure therapy has also been shown effective
for chronic pain, as it reduced pain catastrophizing, fear of
pain, perceived harmfulness of activities, as well as functional
disability (Leeuw et al., 2008;Woods and Asmundson, 2008;
Glombiewski et al., 2018). Another method to reduce conditioned
effects is counterconditioning, during which the US is replaced
by a US of opposite valence. For example, if the CS was
previously paired with an electric shock, this shock could be
replaced during counterconditioning by a monetary reward. This
might lead to more beneficial effects than merely stopping the
reinforcement of the CS as in extinction. Multiple studies have
found counterconditioning to successfully diminish conditioned
effects, but results on the superiority of either extinction or
counterconditioning within the field of fear and evaluative
conditioning are mixed, as shown by a recent review paper
and another recent study (Jozefowiez et al., 2020;Keller et al.,
2020). Additionally, long-term efficacy is not often measured, but
one of the studies did show that during spontaneous recovery
and reinstatement tests (a day after fear induction), diminished
threat expectancy was found in the counterconditioning group
(Kang et al., 2018). However, CS valence did not differ between
the counterconditioning and extinction groups. Furthermore,
another study showed counterconditioning to result in a short-
lived reduction of distress related to the CS+, but this effect
disappeared during later test phases (Hendrikx et al., 2021).
Therefore, it may be worthwhile to investigate long-term effects
of counterconditioning and whether counterconditioning may be
more beneficial in preventing relapse than extinction.
In nocebo research in physical symptoms it has been
shown that conditioned nocebo effects are relatively resistant to
extinction (Colloca et al., 2008;Colagiuri et al., 2015;Colagiuri
and Quinn, 2018) and it may therefore be worthwhile to try
the more active strategy of counterconditioning for reducing
nocebo effects. While studies comparing efficacy of extinction
and counterconditioning for reducing nocebo effects are scarce,
they consistently showed counterconditioning to be superior
to extinction, as counterconditioning can even reverse nocebo
effects into placebo effects (Bartels et al., 2017;Thomaidou et al.,
2020). This finding is also supported by a recent preprint paper
(Meijer et al., 2021). Although these studies are promising, only
healthy participants were examined on the experience of acute
physical symptoms, and the experiments were done in a single
session and in a highly regulated environment, making it difficult
to translate these findings to patients with persistent physical
symptoms in clinical care.
Based on the existing literature on counterconditioning in
fear and evaluative conditioning studies, as well as the limited
knowledge base on experimental counterconditioning in nocebo
studies, a counterconditioning treatment protocol was developed
for application in patients with persistent physical symptoms,
in particular patients with fibromyalgia. As to our knowledge
no other study investigated a counterconditioning treatment
protocol to counteract nocebo effects, it is important to first
study the feasibility and potential effectivity of such a treatment.
Therefore, the current paper describes both the development
and design of a 6-week counterconditioning treatment protocol
aimed to reduce (clinical) pain in patients with persistent
physical symptoms.
METHODS AND ANALYSIS
A 6-week counterconditioning treatment protocol for use in
patients with persistent physical symptoms was developed based
on previous literature on counterconditioning in fear and
evaluative conditioning, as well as the limited literature on
counterconditioning in nocebo effects. The treatment consists of
7 weekly sessions (1 intake session and 6 treatment sessions),
with 2 follow-up appointments 3 and 6 months after end of
treatment. The treatment protocol will be described firstly below.
As this treatment protocol has never been tested before, a first
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study was designed, to test whether patients are able to complete
the protocol and whether there are indications for treatment
efficacy. This study design will be described after the treatment
protocol. When indications for efficacy have indeed been found, a
large-scale randomized controlled trial could be conducted, using
the same methods as described below (potentially with minor
changes based on the results of the first study).
DESIGN OF TREATMENT PROTOCOL
Pain Induction
To be able to test the efficacy of counterconditioning, first a
nocebo effect is induced in all participants, using open-label
nocebo conditioning. To be able to condition a nocebo effect
on pain, pain will have to be induced. In studies on nocebo
pain conditioning, several pain-induction methods could be
chosen. The most commonly used pain-induction methods are
the application of thermal and electrical stimuli. Although these
pain-induction methods are effective in research settings, when
applying (counter)conditioning in pain patients, the choice of
US would ideally be based on the clinical symptoms patients are
experiencing in daily life. While some patients with chronic pain
may experience a burning-like type of pain (e.g., patients with
MS), which resembles thermal pain, or visceral pain (e.g., patients
with IBS), other patients (such as patients with fibromyalgia)
experience a deep-tissue pain, which is more closely resembled
by pressure pain (Wolfe et al., 1990;Gracely et al., 2003;Petzke
et al., 2003). Therefore, in this study pressure pain is used during
the (counter)conditioning procedures.
Pressure pain is induced by applying pressure to the thumbnail
of the non-dominant hand, with a custom-made automated
pneumatic stimulator (named PEPPA), specifically built for
this study by SOLO (Support for Research, Laboratories and
Education, Leiden University). A handpiece is attached to the
stimulator and has a plastic piston that applies pressure via a
1 cm2hard rubber probe. Participants can insert their thumb in
a cylinder opening in the handpiece, after which the probe can
deliver pressure on the middle of the thumbnail. The thumbnail
was selected as a neutral location in which participants feel little
to no clinical pain during testing. As previously reported (Petzke
et al., 2003;Jensen et al., 2009), this is a safe location for repeatedly
delivering pressure stimuli. Stimulus duration is set at 2.5 s,
with an inter-stimulus interval of 30 s. The minimal amount of
pressure administered is 0.5 kg, whereas the maximum is 13 kg.
Finally, an emergency stop is attached to the stimulator, which
participants can press if they cannot tolerate the administered
pain. After pressing the emergency stop button, all air pressure
is released immediately, and they can remove their thumb. All
components of PEPPA are displayed in Figure 1.
Sham Transcutaneous Electrical Nerve Stimulation
Device
A sham Transcutaneous Electrical Nerve Stimulation
(TENS) device (Bentrotens T37, Bentronic Gesellschaft fuer
Medizintechnik GmbH, Wolnzach, Germany) will serve as
nocebo conditioning stimulus (CS) in the first part of the
treatment (the conditioning session), during which it is
FIGURE 1 | Components of PEPPA. 1 shows the main device, 2 the
emergency stop button, and 3 shows the handpiece. The picture on the right
shows how the thumb can be placed into the handpiece.
associated with an increase of pressure pain. During the second
(main) part of the treatment (counterconditioning sessions),
it will again serve as CS, now associated with a reduction of
pressure pain. This device is developed to automatically switch
off after 30 seconds, meaning it will no longer send any electrical
pulses and becomes a sham device. The activation within the
first 30 seconds is according to usual TENS use (i.e., using mild
electrical pulses). Participants are told it is a sham device but are
instructed that it will still have an effect on their pain because of
the placebo effect as has previously been found to be effective in
open-label placebo studies.
Pressure Pain Calibration
To find the optimal pressure intensity for no pain (0-1/10 NRS),
slight pain (2.5-3.5/10 NRS), and moderate pain (5-6/10 NRS),
for the individual participant to be used in the intervention, we
will conduct a calibration procedure consisting of three phases.
For the non-painful stimulus, a minimally painful pressure
intensity (0-1/10 NRS) is accepted, as we expect sensitization
to occur due to repeated pressure administration. In phase 1 of
calibration, pressure stimuli (0.5 kg increments) are applied in
ascending order, up to the first pressure intensity participants
rated as ≥6. In the second phase, five intensities are applied three
times, this time in a random order. The intensities will range
from the highest amount of pressure rated as 0 in phase 1, up
to the highest pressure rated between 5 and 6. If there will not be
any scores between 5 and 6 during phase 1, a formula is used to
calculate the best-fitting value (see Supplementary Appendix 1).
Then, in the third phase, a calibration check is performed. Three
intensities are chosen by taking the median of all intensities that,
during the second phase, are rated within the intended ranges
for no, slight, and moderate pain. If participants will not score
in one or more of the intended ranges, formulas are used to
inter- or extrapolate the best-fitting intensity (see Supplementary
Appendix 1). During the third phase, participants will need
to rate at least one out of two (or two out of three for slight
pain) stimuli within the ranges for no, slight and moderate pain.
If these requirements will not be met, formulas will again be
used to calculate the best-fitting intensity (see Supplementary
Appendix 1). Participants who will not experience enough pain
(i.e., will not rate their pain at least 5/10 at the maximum amount
of pressure), or who will experience too much pain during the
lowest intensity (i.e., will rate their pain above 1 from the lowest
amount of pressure applied), are excluded.
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FIGURE 2 | Procedures used for conditioning and counterconditioning.
Intervention
Nocebo Conditioning
Nocebo conditioning will consist of a learning and testing phase
(see Figure 2). During the learning phase, a message (“ON” or
“OFF”) on the screen in either purple or yellow will indicate the
activation of the TENS device. If the TENS device is indicated
to be on, this is repeatedly paired with a pressure stimulus of
a moderate intensity (5-6/10 on NRS). If the TENS device is
indicated to be off, this is paired repeatedly with a pressure
stimulus of a slightly painful intensity (2.5-3.5 on NRS). The
learning phase will consist of 10 experimental (“ON”) trials
and 10 control (“OFF”) trials, presented in a pseudorandom
order (max 2 stimuli of the same trial type - experimental or
control - follow each other). The testing phase will consist of 3
experimental trials and 3 control trials, again in pseudorandom
order with the same rule. During the testing phase, a slightly
painful stimulus is administered during all trials, regardless of
the message on the screen. The test phase is used to assess
whether a nocebo effect was induced, as would be indicated
by an (on average) higher score on experimental than on
control trials. Additionally, participants are given open-label
suggestions about the conditioning procedure, as they are told
that conditioning is used to teach them that the activation of
the sham device increases their pain, by manually increasing the
intensity of pressure stimuli during experimental trials. They are
also instructed on the nocebo effect and how this will affect their
pain. A detailed description of the suggestions can be found in
Supplementary Appendix 2.
Counterconditioning
Counterconditioning will also consist of a learning and
test phase, similar to nocebo conditioning (see Figure 2).
Counterconditioning is intended to reduce the nocebo effect,
by now repeatedly pairing the alleged TENS activation (ON
trials) with a non-painful stimulus, instead of the moderately
painful stimulus during nocebo conditioning. The procedure
is almost identical to nocebo conditioning, with the only
difference being that now a non-painful (0-1/10 on NRS) pressure
stimulus is paired with activation of the sham TENS device.
The test phase is again used to test whether a nocebo effect
is still present, by comparing experimental and control trials.
Potentially, a placebo effect could be induced, indicated by
an (on average) lower pain score on experimental than on
control trials. Additionally, participants are given open-label
suggestions about the counterconditioning procedure, as they
are told counterconditioning is used to teach them that the
activation of the sham device will now decrease their pain,
by manually decreasing the intensity of pressure stimuli after
experimental trials.
Nocebo effects induced in the lab can be reduced by
counterconditioning in a single session (Bartels et al., 2017;
Thomaidou et al., 2020). However, in clinical care, patients may
have had several negative treatment experiences, instead of a
single occasion as in nocebo conditioning in the lab. This may
make these nocebo effects even more resistant to treatment.
Additionally, as we want to promote long-term efficacy of
the treatment, the counterconditioning procedure is repeated
several times. As literature on the use of counterconditioning (or
related methods, such as systematic desensitization) in clinical
care is limited in the field of fear and evaluative conditioning
(Keller et al., 2020) and non-existent in nocebo research, it is
difficult to determine the optimal number of sessions. Ideally,
the treatment is easily accessible and therefore consist of as
few sessions as possible, while maintaining optimal treatment
efficacy. Therefore, the main intervention during this study will
consist of 6 sessions (1 per week) and 2 follow-up sessions (at 3
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and 6 months after the final session) to boost the intervention
and assess long-term effects. This is much more than previous
lab studies on healthy participants. A first study with this design
will shed light on the course of nocebo reduction (e.g., how
many sessions are needed before the nocebo effect is reduced
and after how many sessions a potential effect on clinical pain
is found). Potentially, this may also differ per person, as we know
susceptibility to nocebo effects also differs between people (Manaï
et al., 2019). Based on this information, the amount of sessions
may be optimized for future applications. If the nocebo effect
is not yet fully reduced after 6 sessions, but a decrease has been
found, the intervention could be expanded with more sessions.
Open-Label Suggestions & Conditioning
One of the most important disadvantages of using traditional
placebo and nocebo conditioning procedures is the fact that
it usually involves deception. During traditional placebo and
nocebo research, participants are not aware of the fact that
the treatment they are receiving is actually a placebo, nor are
they aware a conditioning procedure is used (Benedetti et al.,
2003;Colloca et al., 2008;Bartels et al., 2014, 2017;Colagiuri
et al., 2015;Ba¸bel et al., 2017;Thomaidou et al., 2020,?). While
deception is generally considered acceptable for research, it is
problematic to use deception in clinical care, as patients should
always be fully informed regarding the treatment they are about
to receive (Riddick, 2003). Deception could harm the trust in
both the healthcare professional and the treatment (Miller et al.,
2005;Peerdeman et al., 2021), which could lead to reduced
treatment efficacy and treatment adherence. Open-label placebos
have been examined in several studies (in both healthy and
clinical populations) and have been found to be an effective
treatment (Sandler and Bodfish, 2008;Kaptchuk et al., 2010;
Carvalho et al., 2016;Schaefer et al., 2018;Kleine-Borgmann
et al., 2019); in some studies, open-label placebos were even
as effective as closed-label placebo treatments (Locher et al.,
2017;Lembo et al., 2021). An open-label procedure of nocebo
or placebo conditioning has only been compared to closed-
label procedures once so far, in which no differences were
found between open- and closed-label conditioning (Meeuwis
et al., 2019). Although evidence on the efficacy of open-label
(counter)conditioning is scarce, closed-label suggestions and
(counter)conditioning procedures are not ethically appropriate,
and thus open-label counterconditioning seems the most fitting
option when considering such procedures for reducing nocebo
effects in clinical care. A more detailed description of the
suggestions can be found in Supplementary Appendix 2.
Homework
In between sessions, participants are asked to do homework
exercises to promote generalization of nocebo reduction to
everyday life. Participants are asked to apply at home what they
have learned in the lab, in order to also reduce their clinical
pain symptoms. During the first few weeks, participants will
use the TENS device at home; they are asked to connect the
TENS device to electrodes they will place on their forearm (as
during the lab sessions) and are then asked to think back to
the lab session and how the device influenced their pain during
the session. Then they are asked to imagine the device will now
also influence their clinical pain, anywhere in their body. During
the final weeks, participants will no longer use the TENS and
will instead visualize the function of TENS to reduce their pain.
A detailed description of the homework exercises can be found in
Supplementary Appendix 3.
Study Design
Participants
Participants are females diagnosed with fibromyalgia syndrome
by a general practitioner or medical specialist. Participants must
be at least 18 years old and have a good understanding of written
and spoken Dutch. Exclusion criteria consist of severe somatic or
psychiatric morbidity that may interfere with the study protocol
(e.g., heart/lung diseases), Raynaud’s disease, injuries on the non-
dominant hand, refusal or inability to remove nail polish or
artificial nails on the thumbnail of the non-dominant hand for the
experiment, having metal implants in the non-dominant hand or
arm, having a medicinal pump, and pregnancy or breastfeeding.
Design
A randomized, between-within subjects design is used, with
two groups (see Figure 3 below). Participants are randomly
assigned (1:1) to either the intervention group or the control
group. Participants in the intervention group receives the
counterconditioning intervention, whereas participants in the
control group receives a sham intervention. A randomization list
is made by an independent person and group allocation is noted
down on paper and inserted into an opaque envelope, which is
opened after the pressure pain calibration procedure, to reduce
experimenter bias during calibration. Since all experimental
manipulations contain open-label verbal instructions, neither
the experimenter nor the participant can be fully blinded to
group allocation. Nevertheless, participants are not be explicitly
told whether they are in the intervention or control group. The
intervention consist of seven weekly sessions and two follow-up
sessions (three and six months after the initial seven weeks).
Control Group
A sham intervention can serve as control, meaning a sham
version of both conditioning and counterconditioning can be
used. Sham conditioning and counterconditioning consist of the
same amount of trials as the (counter)conditioning procedures,
with the same intensities of pain administered (see Figure 2).
The major difference is that the pain intensities are not associated
with activation or deactivation of the sham TENS device.
The 20 pain stimuli of each learning phase are presented
randomly, just as the order of the messages (“ON” and “OFF”).
Maximally 2 of the same messages (“ON” or “OFF”) follow each
other. Furthermore, participants are explicitly told there is no
association between the messages and the pain stimuli. More
information on the open-label suggestions will be given below
and in Supplementary Appendix 2.
As for the homework exercises, participants in the control
group also use the TENS device at home during the first weeks,
but participants have not learned a specific association between
the device and pain relief in the lab. They receive a neutral version
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FIGURE 3 | Overview of the treatment protocol for use in patients with persistent physical symptoms, distinguished by group. The (sham) intervention parts of the
procedure are emphasized by using purple dotted lines.
of the task. A detailed description of the homework exercises can
be found in Supplementary Appendix 3.
Self-Report Measures
Several validated questionnaires are filled out by participants,
as well as some questions on their medical history and
demographics. Table 1 gives an overview of all questionnaires
and when they are administered. The Fibromyalgia Impact
Questionnaire (FIQ, (Burckhardt et al., 1991), and a Numeric
Rating Scale (NRS; 0 (no pain) to 10 (worst pain imaginable))
measuring average intensity of clinical pain during the last week
is used to track symptoms of patients throughout the study.
Other measures are used to explore the influence of personal
characteristics (i.e., Pain Catastrophizing Scale (PCS, (Sullivan
et al., 1995)), State and Trait Anxiety Inventory – Trait Scale
(STAI-T, (Spielberger, 1983)), State and Trait Anxiety Inventory –
State Scale, Short Form (STAI-Ss, (Marteau and Bekker, 1992)),
Life Orientation Test Revised (LOT-R, (Scheier et al., 1994))).
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TABLE 1 | Overview of administered questionnaires throughout the intervention.
Time point Questionnaire
Intake session Questions on medical history
Questions on demographics
State-Trait Anxiety Inventory-Trait
Scale Pain Catastrophizing Scale
Life Orientation Test-Revised
Session 1-6, 3- and 6-month
follow ups
Numeric Rating Scale clinical pain
Fibromyalgia Impact Questionnaire
State-Trait Anxiety Inventory-State
Scale Expectations regarding the
intervention
Multiple times during every
session (except intake session)
Numeric Rating Scale on pressure
pain levels Numeric Rating Scale on
valence of CS/control cue
Session 6 + 3- and 6-month
follow-ups
Evaluation questionnaire
Additionally, the expectations participants have regarding the
intervention are measured every session (except for the
intake session). This is measured using 2 questions asking
whether participants believe the intervention will influence 1)
experimentally-induced pain on the thumb and 2) their clinical
pain, using a 0 to 10 numeric rating scale (NRS), with 0 meaning
“will not influence pain at all” and 10 meaning “will very strongly
influence pain”.
Experienced pain throughout the sessions (during calibration
and (counter)conditioning) is measured using an NRS from 0 to
10 (0 indicating no pain, 10 indicating worst pain imaginable on
the hand). Additionally, valence is measured, as it is argued in
studies on fear and evaluative conditioning that the change in
CS valence might be important to prevent reinstatement of the
previously conditioned effects (De Jong et al., 2000;Meulders
et al., 2015;Van Dis et al., 2019). It is therefore important
to investigate whether CS valence is successfully altered by
counterconditioning. Valence of the CS and control cue is
measured after the 1st and 10th trial of the learning phase and
after the 1st trial of the test phase. It is measured using an NRS
ranging from −5 to +5, with −5 meaning “extremely unpleasant”,
0 meaning “neutral” and +5 meaning “extremely pleasant”.
Finally, to measure patient satisfaction, an evaluation
questionnaire is filled out by participants at the end of session
6 and the 3- and 6-month follow-up. This questionnaire includes
questions on the patient-researcher interaction, their satisfaction
regarding the intervention in general, whether the amount of
sessions is feasible, whether they believed the intervention to have
an effect on their pain (both in the lab and at home) and which
group they thought they were placed in.
Procedure
Participants are invited to the lab 9 times (intake session, 6
intervention weeks, 3- and 6-month follow-up). Figure 3 gives
an overview of the procedure.
Screening and Intake
Participants are screened over the phone before inviting them to
the lab, to check whether they are eligible to participate. If eligible,
participants are invited to the lab for a first appointment, the
intake session, in which the intervention is fully explained to the
participants. Additionally, participants are asked to fill in most of
the questionnaires mentioned in Table 1.
Session 1
During session 1, participants fill out several questionnaires (see
Table 1). Afterwards, pain levels are calibrated as described above,
followed by a 5-min break. Subsequently, participants undergo
the nocebo conditioning procedure, which is not repeated in
the other sessions. After nocebo conditioning and a 10-min
break, the counterconditioning procedure follows. The session
is concluded by instructions on the homework exercises, which
participants do daily between the sessions. In total, the duration
of the first session is approximately 2 h.
Session 2-6
During sessions 2 to 6, participants will again fill out several
questionnaires. Then pressure pain calibration is checked by
only repeating phase 3 of the calibration procedure, to ensure
the administered intensities are still perceived similarly to the
first session. If this is not the case, intensities are adjusted using
standard formulas (Supplementary Appendix 1). After a 5-min
break, the counterconditioning procedure will start, after which
the session is concluded. In between sessions, participants will
do daily homework exercises. The duration of session 2-6 is
approximately 35-45 min. Only during session 6, an evaluation
questionnaire is filled out by participants at the end of the session.
Follow Ups
The follow ups are almost identical to sessions 2-6. Again, the
sessions will start with the participants filling out questionnaires,
after which calibration step 3 is repeated. Then, participants
will undergo only a test phase of counterconditioning, to test
long-term effects of the intervention. Through this, it is assessed
whether the nocebo effect is still absent and whether potentially
a placebo effect is still present. After this test phase, the regular
counterconditioning procedure is repeated, to boost the effect of
the intervention. In both follow-up sessions, a short evaluation
questionnaire is filled out at the end of the session. The duration
of both follow-up sessions is approximately 45 min.
Objectives and Statistical Analyses
As the current treatment protocol has never been tested before,
it would be relevant to first test the feasibility of the protocol.
Once proven feasible, a larger randomized controlled trial could
be conducted to test efficacy of the treatment protocol.
The main study parameter in a first study is the feasibility
of the counterconditioning intervention. This can be done
by looking at the drop-out rate; by measuring participants’
satisfaction with the intervention; by examining what, according
to the participants, is causing the possible increase and
reduction of experimentally-evoked pressure pain in the test
phase of (counter)conditioning (e.g., the TENS device, the
placebo or nocebo effect); and by examining the amount of
experimentally-evoked pressure pain reported during the test
phase of counterconditioning, whether this reduces over time, as
well as the speed of this reduction.
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Next to examining the feasibility, a first study could also
exploratively look at indications that the counterconditioning
intervention affects experimentally-evoked pressure pain from
pre- to post-treatment. To this aim, it can be explored whether
the induced nocebo effect in the intervention group can be
successfully reduced (or even reversed) by comparing the
confidence intervals of the change in the conditioned nocebo
effect from the test phase of conditioning (session 1) to the
counter conditioned nocebo effect from the test phase of
counterconditioning (session 6) in the intervention group and
the control group. The effect size and confidence interval of the
difference between groups will also be calculated. Additionally, all
sessions are compared in terms of nocebo reduction, to be able to
assess speed of nocebo reduction.
Confidence intervals of the change in the conditioned nocebo
effect from the test phase of conditioning (session 1) to
the counter conditioned nocebo effect from the test phase
of counterconditioning at 3- and 6-month follow-up in the
intervention group and the control group can also be explored.
The effect size and confidence interval of the difference between
groups are calculated.
Finally, whether there are indications of the influence
of personal characteristics (e.g., expectations regarding the
intervention, amount of anxiety during testing) on the feasibility
of the study and the potential effects of the intervention
can be explored. This is done by comparing the confidence
intervals of the scores on the different questionnaires on personal
characteristics in participants who drop out versus participants
who do not drop out and in participants who show a reduction
of the nocebo effect versus participants who do not show any
treatment effect (within the intervention group).
DISCUSSION
The aim of this paper was to describe a newly-developed
counterconditioning treatment protocol for patients with
persistent physical symptoms and its translation into a study
design of which a first study could test its feasibility and explore
its potential effectiveness. Nocebo effects in clinical care can
have a substantial detrimental impact on treatment outcomes
but cannot always be prevented, therefore it is important to
investigate potential treatment options for reducing nocebo
effects. While counterconditioning has been experimentally
investigated in healthy participants, the proposed treatment
protocol is the first using counterconditioning to reduce
nocebo effects in chronic pain patients (e.g., patients with
fibromyalgia). A first study will provide important insights
on how to potentially further develop this treatment protocol
for reducing nocebo effects in clinical practice. Multiple facets
are considered, such as patient satisfaction, drop-out rate, and
patient characteristics.
Anticipated Results
Feasibility
For a first study, the main outcome parameter is the feasibility
of the treatment protocol. Firstly, drop-out rate can give an
insight into patient satisfaction and into feasibility of completing
the treatment protocol as a patient. While we strive to prevent
drop-out as much as possible, one of the main aims of the
study is to investigate whether it is feasible for patients to
receive this type of treatment weekly, for multiple weeks in a
row. As for patient satisfaction, we aim for participants to be
satisfied with their treatment, by being fully open about the
study procedures (hence the open-label nature of the study).
Nevertheless, we are evoking pain in our protocol, which may
negatively affect patient satisfaction. Furthermore, although the
study is open-label, participants may still be slightly skeptical
about the procedures used, as found in other open-label studies
(Carvalho et al., 2016;Lembo et al., 2021). We strive to reduce this
skepticism as much as possible by providing an explanation of
placebo treatments and how they can be efficacious. Furthermore,
although patients were skeptical and/or expected better results
from active treatments, open-label placebos were still effective
in the aforementioned studies. Finally, we expect participants
to be able to correctly answer what influenced the intensity
of the experimentally-induced pain, which is not the TENS
device itself, but the nocebo or placebo effect (induced by
(counter)conditioning), as we are fully open about the procedure.
Nevertheless, it cannot be ruled out participants may think the
TENS device still has some influence on their pain or that
they attribute their experiences to other phenomena. If this
happens, that might indicate that our instructions regarding
the treatment are not sufficiently clear to participants and
need adjustment.
Efficacy of the Treatment
In a first study, no formal conclusions can be drawn on the
efficacy of the treatment. However, we do expect multiple findings
will point towards successful induction and reduction of nocebo
effects. Firstly, for the treatment group, we expect participants to
score higher on experimental (“TENS on”) trials than on control
(“TENS off”) trials in the test phase of nocebo conditioning
(session 1), which would be in line with other studies on nocebo
conditioning (e.g., Benedetti et al., 2003;Colloca et al., 2008,
2010;Bartels et al., 2014;Colagiuri et al., 2015;Thomaidou
et al., 2020). For the control group, we do not expect to see a
difference between the trial types, similar to results from other
studies using a sham conditioning group (Thomaidou et al.,
2020). Secondly, we expect the nocebo effect (defined as the
average difference between experimental and control trials in
the test phase of conditioning) to be larger in the treatment
group than in the control group. Thirdly, we expect to find a
reduction of the nocebo effect in the treatment group, meaning
the nocebo effect is expected to be (close to) zero or even
below zero (indicating a placebo effect), during the test phase of
counterconditioning in session 6. This is based on the findings
of the few studies investigating counterconditioning for reducing
nocebo effects of physical symptoms in healthy participants
(Bartels et al., 2017;Thomaidou et al., 2020). As for the speed
of this reduction, we will explore whether the nocebo effect can
be reduced from the first session or starting from later sessions,
and whether this reduction is stable throughout the sessions. For
the 3- and 6-month follow-ups, we expect to find similar results,
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Meijer et al. Reducing Nocebo Effects Using Counterconditioning
indicating potential long-term efficacy of counterconditioning.
For the control group, we do not expect to find a change
in effect from conditioning (session 1) to counterconditioning
(session 6 or follow-ups). We also do not expect to find a
placebo effect at the end of session 6 and the follow-ups for
the control group.
Then, regarding valence of the CS, we expect the
counterconditioning procedure to affect the valence from
pre- to post-treatment. During nocebo conditioning (session 1),
we expect participants in the experimental group to rate the CS
more negatively than at the end of counterconditioning (session
6 and both follow-ups). For the control group, we do not expect
to find differences in valence from pre- to post-treatment.
Finally, it can be explored whether the counterconditioning
procedure can be translated to clinical pain. As this is the first
time this is investigated, it is yet to be determined whether
the protocol could be beneficial for reducing clinical pain. We
do, however, expect to find the counterconditioning sessions,
strengthened by the homework exercises, being able to reduce
clinical pain of participants in the treatment group, but not in
the control group.
Should the aforementioned results indeed be found, a large-
scale randomized controlled trial could be conducted afterward,
be able to draw more robust conclusions about the efficacy of the
nocebo counterconditioning treatment.
Anticipated Strengths and Limitations
An important strength of the current treatment protocol
is that it is aimed at reducing existing nocebo effects,
instead of aimed at preventing nocebo effects. Although
arguably the prevention of nocebo effects is crucial in clinical
practice, this is not always feasible, as patients need to
be informed about potential negative effects of a treatment,
which may induce nocebo effects. Consequently, developing
a treatment protocol aimed at nocebo reduction can be of
added value to clinical practice. Another important strength
of this treatment protocol is the fact that an open-label
procedure is used. As mentioned before, traditional paradigms
using (counter)conditioning are mostly deceptive procedures,
which is not suitable for a clinical treatment protocol. As
some studies have already shown the efficacy of open-
label placebos, as well as open-label conditioning, open-label
counterconditioning does seem a promising treatment strategy
for reducing nocebo effects.
Using open-label paradigms may have some disadvantages.
While it is unethical to use deception in clinical practice,
the risk of a response bias may be higher. Participants are
explicitly told (counter)conditioning is used to influence their
pain and this thus makes the intensity of stimuli more
predictable than during traditional paradigms. Furthermore,
they may be more aware of the expected outcomes, which
could also increase the risk of participants answering in a
way fitting the expectations of the researchers. This risk could
be minimized optimally by letting the participants answer
on a computer, instead of directly answering the researcher.
Additionally, nocebo effects are usually not induced in an open-
label fashion, as patients are not aware of the fact they are
being conditioned. Furthermore, instead of a single type of
negative experience, most likely a combination of experiences
has induced nocebo effects in patients. While it is important
to mimic such a negative experience for all participants, it
may be complicated to figure out which stimuli migh be
best used for counterconditioning. Therefore, once proven
potentially effective, the final counterconditioning protocol
may have to be adjusted to account for these differences in
patients’ experiences.
Moreover, the effect of extinction and exposure therapy may
be context-dependent, as found by several studies (Rodriguez
et al., 1999;Mystkowski et al., 2002;Vansteenwegen et al.,
2005). Return of fear appears to be higher in people who were
submitted to a context change after extinction or exposure
than in people remaining within the same context. This may
also be the case for the counterconditioning of the nocebo
effect, but this has not yet been researched. While in the lab
the nocebo effect is induced and reduced within the same
context, this is typically not the case in clinical practice, as the
treatment occurs in a different context than in which effects
were induced. Furthermore, it may prove difficult to translate
effects from the lab or clinic to the home situation, as this
would again be a change of context. By incorporating homework
exercises in between the weekly sessions, we aim to enable
generalization of the effects from the lab to other contexts. The
exploratory results of the study will give insight into whether this
may lead to successful generalization of the effects or whether
alternative and/or extra steps in the protocol are necessary to
promote generalization.
Practical Implications
We expect a first study to show the counterconditioning
intervention to be feasible and will provide preliminary
indications for its effectiveness in relieving pain in fibromyalgia
patients. Should this indeed be observed, a large-scale
randomized controlled trial could be conducted afterward
to assess the efficacy of the counterconditioning protocol.
Results of the first study can help inform the design of
the final protocol, based on the experiences of participants
in the feasibility study and the first indications regarding
treatment efficacy. Additionally, the counterconditioning
protocol should ideally also be compared to other methods
aimed at reducing conditioned responses, to test whether this
method is superior over more commonly used procedures,
such as extinction (exposure therapy), overshadowing,
latent inhibition and blocking (Quinn and Colagiuri,
2018). If shown effective in a larger study, the protocol
could potentially be implemented in clinical practice for
treatment of nocebo effects in patients with persistent physical
symptoms, which could consequently lead to a decrease in these
physical symptoms.
ETHICS STATEMENT
This study was reviewed and approved by the Medical Ethical
Committee Leiden-Den Haag-Delft (number NL 66812.058.18).
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Meijer et al. Reducing Nocebo Effects Using Counterconditioning
Written informed consent was obtained from all participants for
their participation in this study. Furthermore, the study has been
preregistered in the Dutch Trial Register (NL8189).
AUTHOR CONTRIBUTIONS
SM wrote the first draft and all (sub)sections of the manuscript.
SM, HM, KP, and AE contributed to the conception and design
of the treatment protocol and the manuscript and provided
critical feedback on the manuscript. All authors contributed to
manuscript revision, read, and approved the submitted version.
FUNDING
This research was supported by a VICI grant from Netherlands
Organization for Scientific Research (NWO; grant no.
45316004).
SUPPLEMENTARY MATERIAL
The Supplementary Material for this article can be found
online at: https://www.frontiersin.org/articles/10.3389/fpsyg.
2022.806409/full#supplementary-material
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Frontiers in Psychology | www.frontiersin.org 11 June 2022 | Volume 13 | Article 806409