The primary objective is to test the role of NMDA receptor-dependent learning in an experimental model of conditioned nocebo effects on self-reported pain (sub-study 1) and itch (sub-study 2). Secondary objectives are to examine the role of NMDA…
ID
Source
Brief title
Condition
- Other condition
Synonym
Health condition
Nocebo effects (experimental model in healthy participants)
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The main study parameter is the magnitude of induced nocebo effects on
self-reported pain and itch in the evocation phase as compared between the
pharmacological groups. The magnitude of the induced nocebo effects on pain and
itch is measured as the difference between self-reported pain or itch on a
Numeric Rating Scales (NRS) between conditioned and control evocation trials,
in early trials of the extinction phase.
Secondary outcome
Secondary study parameters for both sub-studies:
- The classification accuracy (into pharmacological groups), indicating that
patterns of activation in the network of a priori ROIs form a model that can
detect differences in neural activations during the induction of nocebo effects.
- The classification accuracy (into pharmacological groups), indicating that
patterns of activation in the network of a priori ROIs form a model that can
detect differences in neural activations during the evocation phase.
- The classification accuracy, indicating that patterns of activation in the
network of a priori ROIs form a model that can detect commonalities and
differences in neural activations between the experience of pain and itch.
- The classification accuracy, indicating that patterns of activation in the
network of a priori ROIs form a model that can detect common neural activations
between the experience of nocebo-augmented pain and nocebo-augmented itch,
thereby indicating a signature of activations relevant to the manifestation of
nocebo effects, independent from sensory input.
- The prediction accuracy, indicating that patterns of activation in the
network of a priori ROIs form a model that can predict the magnitude of induced
nocebo effects based on patterns of activations during the induction of nocebo
effects.
- The moderation of the magnitude of induced nocebo effects in the evocation
phase by scores on the psychological questionnaires.
- The magnitude of nocebo effects on pain and itch present after nocebo
attenuation, between the pharmacological groups, as measured in early trials of
the extinction phase relative to the last trials of the extinction phase.
- The classification accuracy (into pharmacological groups) indicating that
patterns of activation in the network of a priori ROIs form a model that can
detect differences in neural activations during the attenuation of nocebo
effects.
Background summary
Nocebo effects, negative responses to inert or active treatments which are
putatively induced by negative outcome expectations, have been shown to play a
significant role in pain and itch perception and putatively also in chronic
pain and itch conditions. The underlying mechanisms of these effects remain
largely unexplored. One important process proposed to be involved in inducing
nocebo effects is conditioning, i.e., associative learning. Nocebo effects on
pain or itch may thus be formed by learning an association between two stimuli,
for example factors in the environment like the treatment setting, and a
negative treatment outcome. Upon conditioning via repeated pairing of these two
stimuli, an association is formed through neural plasticity in the brain.
N-methyl D-aspartate (NMDA) receptor activity appears to mediate the neural
plasticity processes which are thought to underlie learning. Crucially, NMDA
receptors can be agonized with pharmacological agents such as D-cycloserine
(DCS), to augment neural plasticity. The effects of pharmacological
manipulations on NMDA receptor activity can be observed in changes in the blood
oxygen level dependent (BOLD) signal at specific functional regions and in
whole brain networks using functional magnetic resonance imaging (fMRI). By
manipulating NMDA dependent plasticity with this pharmacological agent we will
be able to demonstrate the role of NMDA dependent learning in nocebo effects on
pain and itch.
Study objective
The primary objective is to test the role of NMDA receptor-dependent learning
in an experimental model of conditioned nocebo effects on self-reported pain
(sub-study 1) and itch (sub-study 2). Secondary objectives are to examine the
role of NMDA manipulations and related neural correlates during the induction,
evocation, and attenuation of nocebo effects using statistical learning models.
We also aim to explore neural differences between control stimulations and
nocebo-augmented pain and itch. Lastly, the moderating effects of psychological
variables measured with questionnaires on the nocebo effect will also be
explored.
Study design
This study will utilize a placebo controlled, double-blind design with respect
to the pharmacological administration. We will use validated conditioning and
verbal suggestion paradigms to induce and attenuate nocebo effects on pain or
itch, and examine the pharmacological underpinnings. Participants will be told
that the (sham) activation of electrical pulses is affecting their pain/itch
perception. Experimental pain and itch will be administered using a
standardized thermal heat pain application device (sub-study 1) or through
histamine-evoked itch (sub-study 2). Each sub-study will consist of 2
pharmacological groups: 1) 80mg/70kg DCS oral capsule, 2) a placebo oral
capsule.
Intervention
We will manipulate NMDA-mediated learning mechanisms with a pharmacological
agent, namely, the NMDA receptor agonist D-cycloserine.
Study burden and risks
Risks are minimal. The pharmacological agents are not expected to cause adverse
effects or discomfort to the participants in the doses administered in this
study. Several studies have been conducted in humans with up to 1000mg of DCS
that reported minimal (e.g. drowsiness) or no adverse side effects. All
participants will be monitored by a medical doctor. Mild discomfort or
increased anxiety may be experienced during the induction of heat pain or itch.
The standardized pain application device (Pathway, Medoc) is frequently used in
clinic and research and has built-in safeguards. No risks associated with
topical administration of histamine to evoke itch are known. The fMRI
acquisition is non-invasive and safe. Participants will be carefully screened
for all contra-indications (e.g. metal parts, pregnancy). A medical exam
(carried out by a medical doctor) and a psychiatric screening will be completed
per participant prior to participation. A medical backup team will be on call
to further support the study medical doctor, who will monitor participants at
all times during the study. Participants will be asked to invest approximately
five hours of their time across 2 sessions in order to complete this experiment
and will be allowed to withdraw from the study at any point. Participants will
receive a reimbursement of 90 euros for completion of this study.
Wassenaarseweg 52
Leiden 2333 AK
NL
Wassenaarseweg 52
Leiden 2333 AK
NL
Listed location countries
Age
Inclusion criteria
To be eligible, participants must meet all of the following criteria:
1. Between 18 and 35 years of age
2. Good understanding of spoken and written English
3. Native Dutch speaker
Exclusion criteria
A potential subject who meets any of the following exclusion criteria will be
excluded from participation in this study:
1. History of serious or chronic medical or psychiatric conditions
2. History of chronic pain or itch conditions
3. Experiencing pain or itch on the day of testing above the threshold of 1 out
of 10 on the NRS
4. Currently using antihistamines, analgesic medication, or itch-reducing
medication (in the 24 hours prior to testing)
5. Recent use of psychotropic drugs (including recreational drugs such as
cannabis and psychotropic prescription-medication; in the past month)
6. Currently being (or intending to become) pregnant, or currently breastfeeding
7. Colour-blindness
8. Body Mass Index under 16 or over 30
9. Meeting any exclusion criteria for entering the MR scanner (e.g., permanent
metal parts in the body)
10. Having a too high threshold for pain (where high pain cannot be induced
with temperatures lower than 49.5 °C) or not responding to histamine (no itch
response)
- A medical exam (carried out by a medical doctor) and a psychiatric screening
will be completed per participant prior to participation. A medical backup team
will be on call to further support the study medical doctor, who will monitor
participants at all times during the study.
Design
Recruitment
Medical products/devices used
metc-ldd@lumc.nl
metc-ldd@lumc.nl
metc-ldd@lumc.nl
metc-ldd@lumc.nl
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Other (possibly less up-to-date) registrations in this register
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In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2018-002637-37-NL |
| CCMO | NL66693.058.18 |