Clinical trial NCT03793790: The Role of Learning in Nocebo Hyperalgesia
Official title: Learning Mechanisms in Nocebo Hyperalgesia: the Role of Conditioning and Extinction Processes
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Nocebo Effects
Hyperalgesia
Chronic Pain
Pain Syndrome
Keywords: Nocebo
Pain
Conditioning
Counterconditioning
Partial reinforcement
Learning
Lead sponsor: Leiden University Medical Center
Sponsor class: OTHER
Collaborators: name: Universiteit Leiden
First posted: 2019-01-04
Enrollment: 140
Sex: ALL
Minimum age (years): 18
Maximum age (years): 35
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: This study employs a 2-by-2 design (i.e.,2 conditioning induction groups and 2 attenuation groups), with an additional control group (i.e., sham conditioning). Participants are thus allocated in 1 out of 5 groups.
Primary purpose: BASIC_SCIENCE

Brief summary: Nocebo effects are adverse effects induced by patients' expectations. Nocebo effects on pain may underlie several clinical conditions, such as chronic pain. These effects can be learned via classical conditioning mechanisms. In the lab, nocebo effects are commonly studied via conditioning with continuous reinforcement (CRF) during which 100 percent of unconditioned pain stimuli are paired to conditioned stimuli (i.e., the activation of a mock medical device). Partial reinforcement (PRF) provides a more uncertain pairing during conditioning, where less than 100 percent of unconditioned pain stimuli are paired to conditioned stimuli. This method provides a potentially more clinically relevant learning platform to study how nocebo effects on pain are induced. In this study, the efficacy of conditioning with PRF, CRF, and sham-conditioning in inducing nocebo effects on pain will be compared. Furthermore, a counterconditioning method will be compared to an extinction method for the attenuation of nocebo effects on pain. Given the relevance of nocebo effects for patients, it is important to ascertain effective \& clinically relevant methods to understand how nocebo effects may be formed and attenuated. This study is conducted by Leiden University.

Detailed description: Main planned analyses:

Primary Outcome; Comparing the effectivity of conditioning with PRF, conditioning with CRF, and sham conditioning, in inducing nocebo effects on pain:

The magnitude of the induced nocebo effect during the first evocation phase (dependent variable), will be compared between induction groups (independent variable). The pain ratings for the first control trial will be measured against the pain ratings for the first reinforced trial, yielding the magnitude of the nocebo effect. A 3x2 mixed model Analysis of Variance (ANOVA) will be used, treating group as the between-subjects factor with three levels (PRF, CRF, sham) and magnitude of the nocebo effect on pain as a within-subjects measure with two levels (first control and first reinforced trial). Planned contrasts will be conducted.

Secondary Outcome; Comparing the effectivity of counterconditioning and extinction in attenuating nocebo effects on pain:

The nocebo effect still present in the second evocation phase (dependent variable) will be compared between attenuation groups (independent variable). This effect will be measured as the change in pain ratings reported in the first reinforced trial of the first evocation phase (after induction) and pain ratings reported in the first reinforced trial of the second evocation phase (after attenuation). This effect will be further analysed by measuring any change in pain reports for the control trials (second dependent variable) in the same way. The effect of induction group will also be further explored. A 2x2 mixed model ANOVA will be conducted, with attenuation group as the between-subjects factor (counterconditioning and extinction) and the degree to which the nocebo effect has been attenuated as the within-subjects measure with two levels (first and second evocation phase for the first reinforced trials). Further secondary analyses will be conducted.

Eligibility criteria: Inclusion Criteria:

* Aged 18 - 35 years
* Good understanding of the Dutch language

Exclusion Criteria:

* Severe or chronic physical morbidity (e.g., heart and lung diseases, diabetes)
* Psychiatric disorders (DSM diagnosis; e.g., depression, autism)
* Chronic pain complaints (≥ 6 months) at present or in the past
* Current pain
* Current use of analgesic medication
* Pregnancy
* After inclusion, participants who do not reach a sensation of high pain with the highest temperature administered or participants who appear unable to distinguish between moderate and high pain stimuli will also be excluded

Primary outcomes:
measure: Magnitude of nocebo effects on pain (rated on a 0-10 numeric rating scale) after PRF, CRF, or sham conditioning.
timeFrame: Testing day 1, in the 1st evocation phase
Secondary outcomes:
measure: Magnitude of nocebo effects on pain (rated on a 0-10 numeric rating scale) still present after counterconditioning or extinction.
timeFrame: Testing day 1, in the 2nd evocation phase
Other outcomes:
measure: Possible resistance to extinction of induced nocebo effects on pain (rated on a 0-10 numeric rating scale) after PRF as compared to after CRF.
timeFrame: Testing day 1, in the attenuation phase and the 2nd evocation phase
Locations:
city: Leiden
country: Netherlands
facility: Leiden University
state: South Holland
Study officials:
affiliation: Leiden University Medical Center
name: Andrea WM Evers, Prof. Dr.
role: PRINCIPAL_INVESTIGATOR
References: