The Role of Learning in Nocebo Hyperalgesia

NCT03793790 | Completed

• 1 other identifier: CEP18-0816/318
• Study Type: interventional
• Target: 140
• Locations: 1 country
• Sites: 1

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.

Conditions

Nocebo Effects; Hyperalgesia; Chronic Pain; Pain Syndrome

Keywords

Nocebo; Pain; Conditioning; Counterconditioning; Partial reinforcement; Learning

Outcome Measures

Primary Outcomes (1)

• Magnitude of nocebo effects on pain (rated on a 0-10 numeric rating scale) after PRF, CRF, or sham conditioning.

  This will be calculated in the first evocation phase, by analysing the pain ratings for the first reinforced trial against the pain ratings for the first control trial.

  Testing day 1, in the 1st evocation phase

Secondary Outcomes (1)

• Magnitude of nocebo effects on pain (rated on a 0-10 numeric rating scale) still present after counterconditioning or extinction.

  Testing day 1, in the 2nd evocation phase

Other Outcomes (1)

• 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.

  Testing day 1, in the attenuation phase and the 2nd evocation phase

Study Arms (5)

Group 1

EXPERIMENTAL

Conditioning nocebo effects on pain with a partial reinforcement schedule (induction) and counterconditioning of the previously induced nocebo effect (attenuation).

Behavioral: Conditioning with partial reinforcement; Behavioral: Counterconditioning

Group 2

EXPERIMENTAL

Conditioning nocebo effects on pain with a partial reinforcement schedule (induction) and extinction of the previously induced nocebo effect (attenuation).

Behavioral: Conditioning with partial reinforcement; Behavioral: Extinction

Group 3

EXPERIMENTAL

Conditioning nocebo effects on pain with a continuous reinforcement schedule (induction) and counterconditioning of the previously induced nocebo effect (attenuation).

Behavioral: Conditioning with continuous reinforcement; Behavioral: Counterconditioning

Group 4

EXPERIMENTAL

Conditioning nocebo effects on pain with a continuous reinforcement schedule (induction) and extinction of the previously induced nocebo effect (attenuation).

Behavioral: Conditioning with continuous reinforcement; Behavioral: Extinction

Group 5

SHAM COMPARATOR

Sham conditioning of nocebo effects on pain (induction) and extinction (attenuation).

Behavioral: Sham Conditioning

Interventions

Conditioning with partial reinforcement BEHAVIORAL

Conditioning with partial reinforcement (PRF) provides an uncertain pairing of unconditioned high pain stimuli and conditioned stimuli (i.e., on-screen messages signaling the activation of a mock medical device). During PRF only 70 percent of unconditioned stimuli are paired to conditioned stimuli. Pain of only moderate intensity is used for control stimuli that are paired to the deactivation of the mock device and are also used in the 30 percent of unreinforced trials.

Group 1; Group 2

Conditioning with continuous reinforcement BEHAVIORAL

During conditioning with continuous reinforcement (CRF) unconditioned high pain stimuli are paired to conditioned stimuli (i.e., on-screen messages signaling the activation of a mock medical device) in 100 percent of conditioning trials. Pain of only moderate intensity is used for control stimuli that are paired to the deactivation of the mock device.

Group 3; Group 4

Counterconditioning BEHAVIORAL

During counterconditioning, the previously conditioned nocebo effects on pain are attenuated by pairing the same conditioned stimuli (i.e., on-screen messages signaling the activation of a mock medical device) to thermal pain stimuli of low intensity.

Group 1; Group 3

Extinction BEHAVIORAL

During extinction, the previously conditioned nocebo effects on pain are attenuated by pairing the same conditioned stimuli (i.e., on-screen messages signaling the activation of a mock medical device) only to control stimuli of moderate intensity (previously paired to the deactivation of the mock device).

Group 2; Group 4

Sham Conditioning BEHAVIORAL

In the sham group, participants receive different instructions (namely, that the activation of the device is not expected to affect their pain sensitivity). Additionally, during sham conditioning unconditioned stimuli are not consistently paired to conditioned stimuli, thereby preventing the formation of an association between high pain stimuli and the activation of the mock medical device. In the attenuation phase participants undergo an extinction procedure.

Group 5

Eligibility Criteria

• Age: 18 Years - 35 Years
• Gender Eligibility Details: Participants whose gender identity, gender expression, and lived gender is male, will be included as male. Participants whose gender identity, gender expression, and lived gender is female, will be included as female.
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

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

You may not qualify if:

• 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

Sponsors & Collaborators

• Leiden University Medical Center: lead
• Universiteit Leiden: collaborator

Study Sites (1)

Leiden University

Leiden, South Holland, 2333 AL, Netherlands

Location

MeSH Terms

Conditions

Hyperalgesia; Chronic Pain; Somatoform Disorders; Pain

Interventions

Extinction, Biological

Condition Hierarchy (Ancestors)

Somatosensory Disorders; Sensation Disorders; Neurologic Manifestations; Nervous System Diseases; Signs and Symptoms; Pathological Conditions, Signs and Symptoms; Mental Disorders

Intervention Hierarchy (Ancestors)

Biological Phenomena

Study Officials

• Andrea WM Evers, Prof. Dr.

  Leiden University Medical Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Masking Details: A double-blind randomization list (stratified for gender) was created by an independent statistician. Complete blinding of the researchers during the experiment is not possible due to the nature of conditioning paradigms. However, in this study blinding is optimized: the researchers are informed of the (conditioning) group to which participants are allocated after their final inclusion to the study, and after all questionnaires and pain calibration procedures have been completed on the testing day.
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Prof. Dr.

Model Details: 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.

Study Record Dates

• First Submitted: December 29, 2018
• First Posted: January 4, 2019
• Study Start: September 20, 2018
• Primary Completion: April 30, 2019
• Study Completion: April 30, 2019
• Last Updated: August 13, 2019

Record last verified: 2019-08

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ANALYTIC CODE
• Time Frame: Data will become available immediately after publication of the study and will be retained for 15 years.
• Access Criteria: Data can be shared with scientists in relevant fields for the purpose of future studies such as replication or meta-analysis (or with designated persons for monitoring purposes).

Locations

NL (1)